WO2024259323A2

WO2024259323A2 - Pharmaceutical compositions for targeted delivery of bioactive agents with improved bioavailability and methods of use

Info

Publication number: WO2024259323A2
Application number: PCT/US2024/034128
Authority: WO
Inventors: Scott Shapiro
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-06-14
Filing date: 2024-06-14
Publication date: 2024-12-19
Anticipated expiration: 2025-12-14
Also published as: WO2024259323A3

Abstract

The invention provides therapeutic and pharmaceutical compositions for topical application and targeted delivery of bioactive agents with improved drug bioavailability to a subject, wherein the composition comprises i) an anhydrous carrier; ii) an effective amount of a bioactive agent; and iii) a penetration enhancer selected from the group consisting of an amino acid derivative compound, a cell penetrating peptide (CPP), an antimicrobial peptide, a lipid nanoparticle composition, and combinations thereof.

Description

PHARMACEUTICAL COMPOSITIONS FOR TARGETED DELIVERY OF BIOACTIVE AGENTS WITH IMPROVED BIOAVAILABILITY AND METHODS OF USE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Appl. No.: 63/508,175, filed June 14, 2023, the contents of which are incorporated by reference in their entirety. INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ELECTRONICALLY Incorporated by reference in its entirety herein is a computer-readable sequence listing submitted concurrently herewith and identified as follows: One 44,045 Byte XML file named “CMD-001PCT1.xml,” created on June 14, 2024. FIELD OF THE INVENTION The field of the invention relates to pharmaceuticals and medicine. More particularly, the field of the invention relates to the targeted delivery of bioactive agents, such as topical or transdermal delivery with improved drug bioavailability. BACKGROUND Topical administration of biologically active agents has become an important method for treating a variety of skin conditions. Carlin, Cosmetic Dermatology, February 2001, pp. 35-38 teaches topical administration of vitamin C to reduce erythema of acne rosacea. Greco, Plastic and Reconstructive Surgery 105: 464-465 (2000) suggests the use of topical vitamin C in the treatment of fine wrinkles and as a stimulant for wound healing. Norman and Nelson, Skin and Aging, February 2000, pp. 28-33 teaches topical administration of a variety of common herbs to treat various dermatologic conditions. Unfortunately, many bioactive substances are not efficiently absorbed percutaneously. To overcome this problem, scientists have utilized low pH formulations or derivatives of bioactive substances. However, low pH formulations are irritating to the skin and derivatized compounds, while they may be more efficiently absorbed, are not generally efficiently bioconverted to yield the active compound. In addition, it is frequently difficult to obtain high concentrations of actives in topical formulations, and in aqueous formulations, hydrophobic actives cannot be used. The stratum corneum provides a barrier effect, protecting the body from external substances that might be harmful. In transdermal drug delivery, small molecular weight materials are generally thought to cross the stratum corneum via an intracellular pathway. Large molecular weight materials, on the other hand, utilize an intercellular pathway as well as an intracellular one. Response of the skin to stimuli including pressure, shear, osmotic pressure, heat, or chemicals can cause vasodilation or vasoconstriction, either of which can be planned as a way to adjust skin barrier properties in a desired way as well as targeting drug delivery locally into site-specific tissues or systemically into the bloodstream. Transdermal drug delivery systems have recently been reviewed. Jeong, et al., Recent advances in transdermal drug delivery systems: a review, Biomaterials Research 2021, 25: 24. U.S. Patent No. 9,162,084 describes an anhydrous topical cream delivery formulation for percutaneous absorption. In one embodiment, the formulation consists essentially of capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more of diethylene glycol monoethyl ether, dimethyl isosorbide, propylene glycol, oleic acid, epidermal enzymes, ethanol and dimethylsulfoxide. Despite the effectiveness of the above-described topical cream, the transdermal delivery of some molecules has remained very challenging. There is a great need in the art for topical or transdermal drug delivery compositions that can effectively deliver a broader variety of molecules with improved drug bioavailability to target tissues, especially hydrophilic drugs and drugs with high molecular mass, such as biologics, as these constitute the majority of new drugs and vaccines recently discovered and approved. This background information is provided for informational purposes only. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention. SUMMARY It is to be understood that both the following general description of the invention and the following detailed description are exemplary, and thus do not restrict the scope of the invention. In some aspects, the invention provides pharmaceutical compositions that allow efficient delivery (e.g., transdermal or topical) of effective amounts of bioactive agents for absorption (e.g., percutaneous). In some embodiments, these bioactive agents can include traditionally hard to deliver large hydrophilic molecules such as proteins, peptides and nucleic acids including short interfering RNAs (siRNAs). In some embodiments, the formulations according to the invention are generally non-irritating to the skin or tissue. In one aspect, the invention provides a pharmaceutical composition for topical application for delivery of a bioactive agent to a subject, wherein the composition comprises i) an anhydrous carrier; ii) an effective amount of a bioactive agent; and iii) a penetration enhancer selected from the group consisting of an amino acid derivative compound, a cell penetrating peptide (CPP), an antimicrobial peptide, a lipid nanoparticle composition, and combinations thereof. The composition is applied topically, but the targeted site of action of the bioactive agent is not necessarily located at the topical site of application. In some embodiments, the bioactive agent is absorbed into the systemic circulation and acts distally to the topical site of application. In some embodiments, the composition is for topical (e.g., local skin or other tissues), transdermal (systemic/bloodstream), ocular (local eye), intra-articular (local muskculoskeletal, e.g., tumors, inflammation), intra-tympanic (local ear), or transungual (local through nail plate) delivery. The invention also provides methods of administering the compositions by one or more of these routes to treat a disease or condition in a subject. In some embodiments, the anhydrous carrier comprises one or more esters, amides, ethoxylated fats, mineral oil, petrolatum, vegetable oils, animal fats, triglycerides, polyols (e.g., glycerol), glycerin, propylene glycol, sorbitol, isopropyl myristate and combinations thereof. In some embodiments, the anhydrous carrier comprises glycerin in a concentration of 20-40% (by weight). In some embodiments, the anhydrous carrier comprises capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more diethylene glycol monoethyl ether, dimethyl isosorbide, propylene glycol, oleic acid, epidermal enzymes, ethanol and dimethylsulfoxide. In some embodiments, the anhydrous carrier comprises a combination of glycerin, isopropyl myristate, oleic acid, capric/caprylic triglyceride and diethylene glycol monoethyl ether. In some embodiments, the composition comprises the amino acid derivative compound, wherein the amino acid derivative compound has the following configuration: (AA) ---- (L) ---- (HP), wherein AA is an amino acid or a group of two amino acid molecules linked together by a peptide bond or an alkylene chain linking group having up to six carbon atoms, wherein L is a linker group, and wherein HP is a hydrophobic moiety. In some embodiments, HP is an alkyl or alkenyl hydrocarbon chain having a length of from 10 to 20 carbon atoms. In some embodiments, L is selected from the group consisting of a single bond, a carbonyl group, -C(O)-O-CH2, -C(O)-O-CH2CH2-, -C(O)-NH-CH2- and – C(O)-NH-CH2CH2-. In some embodiments, the amino acid(s) are selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, 6-(dimethylamino)hexanoic acid, derivatives thereof, and combinations thereof. In some embodiments, the amino acid derivative is selected from a compound identified in Table 1, or a combination thereof. In some embodiments, the composition comprises a cell penetrating peptide. In some embodiments, the peptide consists of six to twenty amino acid residues. In some embodiments, at least 50% of the amino acid residues of each peptide are positively charged at physiological pH. In some embodiments, the positively charged amino acid residues are selected from arginine and lysine. In some embodiments, at least one of the permeation enhancer peptide is an antimicrobial peptide. In particular embodiments, the antimicrobial peptide can be magainin or a derivative of magainin. In some embodiments, the derivative of magainin can be magainin substituted by a dipeptide. In some embodiments, the dipeptide derivative of magainin can be magainin substituted by Gly-Ala. In some embodiments, the dipeptide derivative of magainin can be magainin substituted by Lys-Leu. In some embodiments, the antimicrobial peptide is a magainin peptide. In some embodiments, the cell penetrating peptide is selected from the group consisting of any of SEQ ID NOS:1-49 and combinations thereof. In some embodiments, the composition comprises a lipid nanoparticle composition. In some embodiments, the lipid nanoparticle (LNP) composition comprises one or more cationic lipids. In some embodiments, the bioactive agent is selected from a biologic, protein, vaccine, macromolecule, and a small molecule. In some embodiments, the bioactive agent is an antibody. In some embodiments, the LNPs can be employed in combination with amino-based peptides for transdermal delivery of protein drugs, biologics and vaccines. In another aspect, the invention provides a method of treating a disease or condition in a subject, comprising administering to the subject’s skin an effective amount of a topical pharmaceutical composition as provided herein. In some embodiments, effective amounts of the bioactive agent are absorbed into the subject’s blood circulation. In some embodiments, the method further comprises exfoliating the skin of the subject prior to the administering step. In some embodiments, the present invention provides a composition for facilitating transdermal delivery of biologics, proteins, macromolecules, nucleic acids, or small molecules, the composition comprising an anhydrous topical cream delivery formulation for percutaneous absorption comprising one or more of i) capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more azone, urea, pyrrolidones, essential oils, terpenes and terpenoids, oxazolidinones, propylene glycol, epidermal enzymes, oleic acid, dimethyl isosorbide, sulphoxides, dimethylsulfoxide, dimethylsulfone, ethanol, diethylene glycol monoethyl ether, hyalauronic acid, chitin, mucopolysaccharides, fatty acids, linoleic acid, alpha linoleic acid, cod liver oil, menthol, menthol derivatives, squalene, glycerol derivatives, and glycerol monoethers, ii) a bioactive substance and iii) a penetration enhancer selected from the group consisting of an amino acid derivative compound, a cell penetrating peptide (CPP), an antimicrobial peptide, a lipid nanoparticle composition, and combinations thereof. In some embodiments, the diameters of the lipid nanoparticles can be within a range of from about 10 nm to about 60 nm. In some embodiments, the compositions comprise an anhydrous carrier medium, a an effective amount of a bioactive agent, a penetration enhancer and optionally an exfoliant. Such formulations are free of any occlusive agent that prevents percutaneous absorption. In another aspect, the invention provides methods for using the formulations according to the invention to treat a dermatologic condition, the methods comprising applying therapeutically effective amounts of the formulations according to the invention to the skin. In another aspect, the invention provides a method for treating a dermatologic condition, the method comprising exfoliating the skin and applying to the skin a topical pharmaceutical composition as described herein. In some embodiments, the composition comprises an exfoliant. In another aspect, the invention provides a method for introducing a bioactive agent into the blood circulation of a subject. The method according to this aspect of the invention comprises applying therapeutically effective amounts of the topical pharmaceutical composition according to the invention to the subject’s skin. In another aspect, the invention provides a method for introducing a bioactive agent into the blood circulation of a subject. The method according to this aspect of the invention comprises exfoliating the skin of a subject and applying to the skin a topical pharmaceutical composition according to the invention. In some embodiments, compositions according to the invention can comprise an anhydrous carrier medium, an effective amount of bioactive agent and a skin permeation enhancer material. In another aspect, the invention provides a method for introducing a bioactive agent into a limited local region of a subject’s body. The method according to this aspect of the invention comprises applying therapeutically effective amounts of the topical pharmaceutical composition according to the invention to the subject’s skin. In some embodiments, the bioactive agent acts locally in the subject’s deep tissues including, without limitation, tumors or the musculoskeletal system, such as muscles, joints, tendons, ligaments, or bone. In another aspect, the invention provides a method for introducing a bioactive agent into a limited local region of a subject’s body. The method according to this aspect of the invention comprises exfoliating the skin of a subject and applying to the skin a therapeutically effective amount of the topical pharmaceutical composition according to the invention. In some embodiments, compositions according to the invention can comprise an anhydrous carrier medium, an effective amount of bioactive substance and a skin permeation enhancer material. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1. Anatomy of the human skin and possible routes for cutaneous drug delivery. Diagrammatic representation of the 3 compartments of the skin as they relate to drug delivery: surface, stratum (Str.), and viable tissues. After application of a drug to the surface, evaporation and structural/compositional alterations occur that determine the drug’s bioavailability. The stratum corneum limits diffusion of compounds into the viable skin and body. After absorption, compounds either bind targets in viable tissues or diffuse within the viable tissue or into the cutaneous vasculature, and reach internal cells and organs via the systemic circulation. Adapted from Dermatological Pharmacology (https://basicmedicalkey.com/dermatological-pharmacology-2/). FIG. 2. Growth curve of Wistar rats per Charles River Labs. FIG. 3. Example of the use of microneedle arrays in rats. FIG. 4. Schematic illustration of the skin in mouse and humans. Left: murine skin structure. Mouse skin has a high density of fibroblasts (blue and purple). The panniculus carnosus is under the hypodermis. Right: human skin structure. Human skin structure differs from that of mouse. The epidermis is thicker and forms ingrowths called rete ridges (RR). Hair follicle density in human skin is lower than in mouse. APM, arrector pili muscle; BM, basement membrane; DP, dermal papillae; DS, dermal sheath; DWAT, dermal white adipose tissue; EP, epidermis; ESG, eccrine sweat gland; HD, hypodermis; HF, hair follicle; PC, panniculus carnosus; PD, papillary dermis; RD, reticular dermis; SG, sebaceous gland (adapted from Summerfield et al., 2015). FIG. 5. Biotin Concentration in Rat Plasma Pre and Post Treatment. FIG. 6. Biotin Concentration in Rat Plasma Pre and Post Treatment. DETAILED DESCRIPTION Percutaneous, transdermal or topical drug delivery has become an attractive alternative to systemic injection using needles. Local delivery at a controlled rate means that an undesirably high local concentration of the drug is avoided, and the drug can be targeted to tissues where it is needed and minimized where it is not needed. The passage of drugs through the intestinal tract can be avoided, and unwanted degradation of a drug through metabolism, the effects of different pH environments, or interaction with digestive enzymes or intestinal bacteria can be avoided. Topical and transdermal drug delivery is noninvasive and generally involves minimal pain and burden on the patient, so vulnerable populations can readily be served. Compared to the commonly used method of drug delivery by injection, transdermal drug delivery generates lower amounts of hazardous medical waste and presents a lower risk of disease transmission by needle re-use. Patient compliance with transdermal drug delivery methods is generally good, and drug administration can be sustained over a long period of time and/or varied in a desired way over time. The present invention provides compositions and methods for topical application for targeted delivery of bioactive agents with improved drug bioavailabilty. More effective drug delivery to target tissues results in a greater therapeutic effect. Drugs with a molecular mass larger than 500 Da are hindered primarily by low skin permeability. In some embodiments, the present invention provides anhydrous carriers in combination with certain permeation enhancers selected from amino acid derivatives, cell penetrating peptides, or lipid nanoparticles, or combinations thereof, to increase drug flux through the skin or other tissues into the systemic circulation. Reference will now be made in detail to embodiments of the invention which, together with the following examples, serve to explain the principles of the invention. These embodiments describe in sufficient detail to enable those skilled in the art to practice the invention, and it is understood that other embodiments may be utilized, and that structural, biological, and chemical changes may be made without departing from the spirit and scope of the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used). The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of” and/or “consisting of.” As used herein, the term “about” means at most plus or minus 10% of the numerical value of the number with which it is being used. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. One skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include, for example, Transdermal Drug Delivery: Revised and Expanded (Drugs and the Pharmaceutical Sciences, vol. 123), R.H. Guy and J. Hadgraft, eds., CRC Press, 2nd ed., 2003; Topical and Transdermal Drug Delivery: Principles and Practice, H.A.E. Benson and A.C. Watkinson, eds., Wiley, 1st ed., 2012; Dermal Drug Delivery: From Innovation to Production, T.K. Ghosh, ed., CRC Press, 1st ed., 2020; Advanced Electroporation Techniques in Biology and Medicine (Biological Effects of Electromagnetics), A.G. Pakhomov, D. Miklavcic and M.S. Markov, eds., CRC Press, 1st ed., 2010; N. Washington, et al., Physiological Pharmaceutics: Barriers to Drug Absorption, CRC Press, 2nd ed., 2001; Dermatotoxicology Methods: The Laboratory Worker’s Ready Reference, F.N. Marzulli and H.I. Maibach, eds., Taylor & Francis, 1998; A.C. Williams, Transdermal Drug Delivery: From Theory to Clinical Practice, Pharmaceutical Press, 2003; D. Bhowmik, et al., Recent Advances in Transdermal Drug Delivery System, LAP LAMBERT Academic Publishing, 2017; Mechanisms of Transdermal Drug Delivery, R.O. Potts, ed., Informa Healthcare, 1st ed., 1997; P. Gaur, et al., Topical and Transdermal Drug Delivery System: Emerging Trends and Prospects, Lambert Academic Publishing, 2012; V. Singh, et al., Formulation Variables of Transdermal Drug Delivery Systems: Transdermal Gels, Lambert Academic Publishing, 2010; V.S. Kulkarni, Handbook of Non- Invasive Drug Delivery Systems: Science and Technology (Personal Care and Cosmetic Technology), William Andrew, 1st ed., 2009; H.K. Patel, et al., Penetration Enhancers: An Important Tool for Transdermal Drug Delivery: Enhancement in Drug Delivery, Lambert Academic Publishing, 2012; A.K. Banga, Transdermal and Intradermal Delivery of Therapeutic Agents: Application of Physical Technologies, CRC Press, 1^st ed., 2011; Drug Delivery: Fundamentals and Applications, A.M. Hillery and K. Park, eds., CRC Press, 2nd ed., 2016; Percutaneous Penetration Enhancers: Drug Penetration Into/Through the Skin, N. Dragicevic and H.I. Maibach, eds., Springer, 1st ed., 2017; Enhancement in Drug Delivery, E. Touitou and B.W. Barry, eds., CRC Press, 1st ed., 2006; Drug Delivery Nanoparticles Formulation and Characterization (Drugs and the Pharmaceutical Sciences Book 191), Y. Pathak and D. Thassu, eds., Informa Healthcare, 2009; and Skin Delivery Systems: Transdermals, Dermatologicals, and Cosmetic Actives, J.J. Wille, ed., Wiley- Blackwell, 1^st ed., 2006. The term “active form” with respect to a bioactive agent or drug refers to a form in which it is capable of performing its physiological or therapeutic role. The term “antimicrobial peptide” refers to a peptide, generally of 10 to 100 amino acid residues, that differentiates between bacterial cells and mammalian cells in its ability to alter cell membrane permeability and cause cell lysis and death. The term “cathelicidine” refers to a class of amphiphilic antimicrobial peptides that kills bacterial pathogens by disintegrating, damaging, or puncturing cell membranes. Cathelicidines are natural peptides that have been isolated from a variety of mammalian species. The term “magainin” refers to a member of a class of cationic antimicrobial peptides that have been isolated from the African clawed frog, Xenopus laevis. The term “percutaneous drug delivery” refers to penetration of the stratum corneum by a bioactive agent. As used herein, the term "about" means plus or minus 10% of the numerical value of the number with which it is being used. The terms "nucleic acid," and "polynucleotide," are used interchangeably and refer to a deoxyribonucleotide or ribonucleotide polymer, in linear or circular conformation, and in either single- or double-stranded form. For the purposes of the present disclosure, these terms are not to be construed as limiting with respect to the length of a polymer. The terms can encompass known analogues of natural nucleotides, as well as nucleotides that are modified in the base, sugar and/or phosphate moieties. The terms "polypeptide," "peptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues. The term also applies to amino acid polymers in which one or more amino acids are chemical analogues or modified derivatives of corresponding naturally-occurring amino acids. The term "sequence" relates to a nucleotide sequence of any length, which can be DNA or RNA; can be linear, circular or branched and can be either single-stranded or double stranded; and also can include an amino acid sequence of any length. The term "identity" relates to an exact nucleotide-to-nucleotide or amino acid-to- amino acid correspondence of two polynucleotides or polypeptide sequences, respectively. Two or more sequences (polynucleotide or amino acid) can be compared by determining their percent identity. Calculations of homology or sequence identity between two sequences (the terms are used interchangeably herein) are performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The optimal alignment is determined as the best score using the GAP program in the GCG software package with a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frame shift gap penalty of 5. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences. "Sequence similarity" between polynucleotides can be determined by hybridization of polynucleotides under conditions that allow formation of stable duplexes between homologous regions, followed by digestion with single-stranded-specific nuclease(s), and size determination of the digested fragments. The term “treating” or “treatment”, as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. A “therapeutically effective amount” or “effective amount” refers to a minimal amount of therapeutic agent which is necessary to impart therapeutic benefit to a subject. For example, a “therapeutically effective amount” to a mammal is such an amount which induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression or physiological conditions associated with or resistance to succumbing to a disorder. The terms "treating" and "treatment" as used herein refer to administering to a subject a therapeutically effective amount of a composition so that the subject has an improvement in the disease or condition. The improvement is any observable or measurable improvement. Thus, one of skill in the art realizes that a treatment may improve the patient's condition, but may not be a complete cure of the disease. Treating may also comprise treating subjects at risk of developing a disease and/or condition. “Bioactive agent” or “therapeutic agent” refers to a chemical compound or other composition, such as a protein, antigen, antibody, nucleic acid, or small molecule capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject. For example, therapeutic agents for cancer include agents that prevent or inhibit development or metastasis of cancer, either acting alone, or in combination with other agents. The term "antibody" means an immunoglobulin molecule (or antigen binding sequence thereof) that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, the term "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, antibody fragments (such as Fab, Fab', F(ab')2, and Fv fragments, dual affinity retargeting antibodies (DART)), single chain Fv (scFv) mutants, single domain antibodies (nanobodies), multispecific antibodies such as bispecific and trispecific antibodies generated from at least two intact antibodies, chimeric antibodies, humanized antibodies, human antibodies, fusion proteins comprising an antigen determination portion of an antibody, and any other modified immunoglobulin molecule comprising an antigen recognition site so long as the antibodies exhibit the desired biological activity. In some embodiments, an antibody can be of any the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g. IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively. The different classes of immunoglobulins have different and well known subunit structures and three-dimensional configurations. Antibodies can be naked or conjugated to other molecules such as toxins, radioisotopes, etc. The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 basic heterotetramer units along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain. In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable region (V_H) followed by three constant domains (C_H) for each of the α and γ chains and four CH domains for µ and ε isotypes. Each L chain has at the N-terminus, a variable region (VL) followed by a constant domain (CL) at its other end. The VL is aligned with the VH and the CL is aligned with the first constant domain of the heavy chain (C_H1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable regions. The pairing of a V_H and V_L together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn., 1994, page 71, and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains (C_L). Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (µ) respectively. The γ and α classes are further divided into subclasses on the basis of relatively minor differences in C_H sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The terms "antigen" or "immunogen" are used interchangeably to refer to a substance, typically a protein, which is capable of inducing an immune response in a subject. The term also refers to proteins that are immunologically active in the sense that once administered to a subject (either directly or by administering to the subject a nucleotide sequence or vector that encodes the protein) is able to evoke an immune response of the humoral and/or cellular type directed against that protein. A "monoclonal antibody" refers to a homogeneous antibody population involved in the highly specific recognition and binding of a single antigenic determinant, or epitope. This is in contrast to polyclonal antibodies that typically include different antibodies directed against different antigenic determinants. The term "monoclonal antibody" encompasses both intact and full-length monoclonal antibodies as well as antibody fragments (such as Fab, Fab', F(ab')2, Fv), single chain (scFv) mutants, fusion proteins comprising an antibody portion, and any other modified immunoglobulin molecule comprising an antigen recognition site. Furthermore, "monoclonal antibody" refers to such antibodies made in any number of manners including but not limited to by hybridoma, phage selection, recombinant expression, and transgenic animals. The term "humanized antibody" refers to forms of non-human (e.g. murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human (e.g., murine) sequences. Typically, humanized antibodies are human immunoglobulins in which residues from the complementary determining region (CDR) are replaced by residues from the CDR of a non-human species (e.g. mouse, rat, rabbit, hamster) that have the desired specificity, affinity, and capability (Jones et al., 1986, Nature, 321:522-525; Riechmann et al., 1988, Nature, 332:323-327; Verhoeyen et al., 1988, Science, 239:1534-1536). In some instances, the Fv framework region (FR) residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species that has the desired specificity, affinity, and capability. The humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or capability. In general, the humanized antibody will comprise substantially all of at least one, and typically two or three, variable domains containing all or substantially all of the CDR regions that correspond to the non-human immunoglobulin whereas all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. Examples of methods used to generate humanized antibodies are described in U.S. Pat. No. 5,225,539 or 5,639,641. The terms “subject” and “patient” are used interchangeably herein, and refer to an animal such as a mammal. In general, the terms refer to a human. The terms also includes domestic animals bred for food, sport, or as pets, including horses, cows, sheep, poultry, fish, pigs, cats, dogs, and zoo animals, goats, apes (e.g. gorilla or chimpanzee), and rodents such as rats and mice. Typical subjects include persons susceptible to, suffering from or that have suffered from a disease or condition. In some embodiments, the invention relates to compositions for topical application for delivery of bioactive agents and methods of treating diseases or conditions by administering the same. Pharmaceutical compositions topically applied to the subject for targeted delivery are selected from the group consisting of compositions applied to local skin (and other tissues), transdermal (systemic/bloodstream), ocular (local eye tissues), intra-articular (local joints), musculoskeletal (local muscle, tendons, ligaments, joints), intra-tympanic (local into the ear), transungual (through nail plate into nail bed), and combinations thereof. In some embodiments the compositions are formulated as creams, ointments, pastes, lotions, liquid solutions, or liquid suspensions. In some embodiments, the invention relates to anhydrous formulations for percutaneous absorption that comprise one or more permeation enhancers as described herein. In one embodiment, the invention provides a composition for facilitating topical or transdermal delivery of bioactive agents, such as biologics, proteins, macromolecules, nucleic acids, and small molecules. In one embodiment, the invention provides a pharmaceutical composition for topical application for delivery of a bioactive agent to a subject, wherein the composition comprises i) an anhydrous carrier; ii) an effective amount of a bioactive agent; and iii) a penetration enhancer selected from the group consisting of an amino acid derivative compound, a cell penetrating peptide (CPP), an antimicrobial peptide, a lipid nanoparticle composition, and combinations thereof. In some embodiments, the composition is for topical, transdermal, ocular, intra- articular, musculoskeletal, intra-tympanic, or transungual delivery. In some embodiments, the amount of the anhydrous carrier that is present in the composition is from about 70% to about 99% by weight of the composition. In some embodiments, the amount of the anhydrous carrier that is present in the composition is from about 90% to about 95% by weight of the composition. In some embodiments, the anhydrous carrier is selected from glycerin, oleic acid, capric/caprylic triglyceride diethylene glycol monoethyl ether, and a combination thereof. In some embodiments, the amount of the bioactive agent that is present in the composition is from about 0.001% to about 5% by weight of the composition. In some embodiments, the amount of the bioactive agent that is present in the composition is from about 0.05% to about 2% by weight of the composition. In some embodiments, the bioactive agent is a monoclonal antibody or a fragment thereof. In some embodiments, the bioactive agent is an antibody. In some embodiments, the bioactive agent is an antibody-drug conjugate (e.g., antibody conjugated to a cytotoxic molecule). In some embodiments, the amount of the penetration enhancer that is present in the composition is from about 0.3% to about 10% by weight of the composition. In some embodiments, the amount of the penetration enhancer that is present in the composition is from about 1% to about 3% by weight of the composition. In some embodiments, the penetration enhancer comprises a cell penetrating peptide (CPP).In some embodiments, the invention provides formulations that allow efficient delivery of effective amounts of bioactive substances for percutaneous absorption. The formulations according to the invention are generally non-irritating to the skin, which may cause slight tingling of a passive nature due to the heightened activity. In some embodiments, the compositions according to the invention provide many advantages over aqueous formulations. For example, acidic or basic biological actives in an aqueous environment will at high concentrations affect the pH of the formulation, thus rendering it irritating to the skin. In an anhydrous environment, ionization does not occur, so high concentrations of such actives may be achieved in a formulation that does not irritate the skin. This is advantageous because one of the governing factors for percutaneous absorption is the concentration of the biological active, with higher concentrations leading to increased percutaneous absorption. In some embodiments, the bioactive agents are highly stable in the anhydrous compositions. In some embodiments, amino acid derivatives and/or cell-penetrating peptides have a hydrophobic “tail” attached to an amino acid “head” via an ester linkage. Ester bonds can be hydrolyzed (i.e. broken) by water. The anhydrous formulation with no water present is favorable in terms of stability (preserving compound integrity over time during storage), compared to aqueous formulations. In some embodiments, the combination of the anhydrous carrier and permeation enhancer achieves a synergistic effect on delivery of the bioactive agent compared with either the carrier or permeation enhancer alone. In some embodiments, the compositions provide a further advantage of providing the biological active agent in a particle size in proportion to the molecular size of the biological active. This is advantageous because the size of the biological active is another governing factor for percutaneous absorption. As particle size decreases, percutaneous absorption increases. In some embodiments, another advantage provided by the anhydrous compositions according to the invention is increased stability of the biological active. Hydrophilic biological actives are frequently labile when exposed to water. They are prone to oxidation, hydrolysation and decomposition. In the formulations according to the invention, they are not. Also, in some embodiments of the invention, this stability is further enhanced by coating the molecular-sized particles with protective oils. This allows non-derivatized (i.e., not covalently modified) biological actives to be used and prevents coalescence of particles. Since bioconversion of covalently derivatized biological actives is generally inefficient, this provides greater activity for the biological active. In some embodiments, yet another advantage provided by the anhydrous compositions according to the invention is that they efficiently partition hydrophilic biological actives for percutaneous absorption, because the hydrophilic molecules prefer the hydrophilic environment of the dermis to the hydrophobic environment of the anhydrous formulation. In some embodiments, an additional advantage provided by the compositions according to the invention is that they can exfoliate the skin as they are applied. By removing dead skin cells of the stratum corneum without damaging underlying keratinocytes and fibroblasts, percutaneous absorption is further enhanced. In some embodiments of the invention, this effect is increased through the use of penetration enhancers that reversibly alter the physiochemical nature of the stratum corneum to reduce its diffusional resistance. In some embodiments, the invention provides formulations that are capable of efficient percutaneous absorption of high concentrations of hydrophobic, hydrophilic or amphoteric bioactive substances. A great variety of bioactive substances may be included in the formulations according to the invention. In some embodiments, the formulations according to the invention comprise an anhydrous carrier medium, an effective amount of micronized or nanosized bioactive substance, an exfoliant, and a penetration enhancer herein. Such formulations are preferably free of any occlusive agent that prevents percutaneous absorption, such as silicones. In preferred embodiments the micronization may be wet micronization or dry micronization. For purposes of the invention, an “anhydrous carrier medium” is a substance that is free of water. Preferred anhydrous carriers include, without limitation, esters, amides, ethoxylated fats, mineral oil, petrolatum, vegetable oils, animal fats, triglycerides, polyols (e.g., glycerol), glycerin, propylene glycol, isopropyl myristate and sorbitol. Glycerin in concentrations of 5-40%, 25-35% and about 35% are among the preferred embodiments. In certain preferred embodiments the exfolient is non-irritating. In certain preferred embodiments the bioactive substance is non-derivitized. In some embodiments, the compositions may be manufactured by standard “dry” micronization or nanosizing (particle size reduction) processes. According to certain preferred methods of manufacturing the preferred formulations, the bioactive substance, preferably in powder form is subjected to a “wet” micronization or nanosizing process, as made available by Microniser Pty. Ltd. of Dandenong, Australia/Micronisers of Australia of Melbourne, Australia. Wet micronization or nanosizing prevents overheating of the active, the coating prevents coalescence of particles and protects against oxidation, reduction and hydrolysis. This process, which may be contrasted to so-called “dry” or standard particle size reduction processes, preferably involves the grinding of the powder, suspended in or otherwise in the presence of a non-aqueous liquid, preferably an oil (hereinafter, the “suspending medium”). In some embodiments, the process is preferably conducted in an abrasion-resistant container in the presence of a grinding medium, using sufficiently high rpm for a sufficiently long duration, and a suitable stirrer. The resulting suspension may be separated from the grinding medium by suction filtration of the powder. This micronization or nanosizing process is capable of producing particles of bioactive substance having a mean particle size corresponding to the molecule size of the bioactive substance. Alternatively, the grinding may be conducted in the presence of 0.1 to 30%, and preferably 0.5 to 15% by weight, of a grinding aid such as an alkylated vinylpyrrolidone polymer, a vinylpyrrolidone-vinylacetate copolymer, an acylglutamate, an acrylate-tert.- octylpropenamide copolymer, a ditolylether sulphonic acid-formaldehyde condensate, a carbomer, a commercial mixture of fatty acid esters comprising a nonionic precursor such as tristyrylphenol ethoxylate or, in particular, a phospholipid, as described in U.S. Pat. No. 5,869,030. In some embodiments, the suspending medium is most preferably a vegetable oil, which promotes (along with the physical micronization or nanosizing process, as described above) breaking the bioactive substance into ultrafine particles and, at the same time, coating the particles with the oil, which promotes maximum absorbance and stability of the bioactive substance in the formulation. The micronized bioactive substance particles used preferably exhibit a mean particle size of no more than approximately 5 μm, and preferably a mean particle size of in the range of from about 0.01 to about 2 μm, and most preferably from about 0.05 to about 1.5 μm, and especially from about 0.1 to about 1.0. μm. Oils most preferable and therefore most suitable for use include, without limitation, caprylic triglycerides, capric triglycerides, isostearic triglycerides, adipic triglycerides, propylene glycol myristyl acetate, lanolin oil, polybutene, isopropyl palmitate, isopropyl myristate, diethyl sebacate, diisopropyl adipate, hexadecyl stearate, cetyl oleate, oleyl alcohol, hexadecyl alcohol, wheatgerm oil, vegetable oils such as castor oil, corn oil, cottonseed oil, olive oil, palm oil, coconut oil, palm kernel oil, canola oil, sunflower oil, safflower oil, meadow foam oil, jojoba oil, hydrogenated vegetable oils, and mineral oil. In one preferred embodiment, the bioactive substance is micronized in the presence of capric/caprylic glycerides in which the bioactive substance is present at high concentration. In some embodiments, the anhydrous carrier comprises one or more esters, amides, ethoxylated fats, mineral oil, petrolatum, vegetable oils, animal fats, triglycerides, polyols (e.g., glycerol), glycerin, propylene glycol, sorbitol, isopropyl myristate and combinations thereof. In some embodiments, the anhydrous carrier comprises glycerin in a concentration of about 20-40%. In some embodiments, the anhydrous carrier comprises one or more of capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more azone, urea, pyrrolidones, essential oils, terpenes and terpenoids, oxazolidinones, propylene glycol, epidermal enzymes, oleic acid, dimethyl isosorbide, sulphoxides, dimethylsulfoxide, dimethylsulfone, ethanol, diethylene glycol monoethyl ether, hyalauronic acid, chitin, mucopolysaccharides, fatty acids, linoleic acid, alpha linoleic acid, cod liver oil, menthol, menthol derivatives, squalene, glycerol derivatives, and glycerol monoethers, In some embodiments, the present invention provides a composition for facilitating transdermal delivery of biologics, proteins, macromolecules and small molecules, the composition comprising an anhydrous topical cream delivery formulation for percutaneous absorption consisting essentially of capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more azone, urea, pyrrolidones, essential oils, terpenes and terpenoids, oxazolidinones, propylene glycol, epidermal enzymes, oleic acid, dimethyl isosorbide, sulphoxides, dimethylsulfoxide, dimethylsulfone, ethanol, diethylene glycol monoethyl ether, hyalauronic acid, chitin, mucopolysaccharides, fatty acids, linoleic acid, alpha linoleic acid, cod liver oil, menthol, menthol derivatives, squalene, glycerol derivatives, and glycerol monoethers,, a bioactive substance and a penetration enhancer as described herein. The bioactive agent in the composition and which can be administered to a subject is not limiting. In some embodiments, the bioactive agent(s) is one or more biologics, proteins (e.g., insulin), vaccines, antibodies (such as a monoclonal or humanized antibodies), macromolecules, nucleic acids (such as mRNAs, siRNAs, antisense RNAs, shRNAs, or oligonucleotides), or small molecules (e.g., chemotherapeutics). In some embodiments, the bioactive agent is an antibody. In some embodiments, the bioactive agent is a therapeutic oligonucleotide, including antisense oligos (ONs), siRNA, and microRNA mimics and inhibitors. In some embodiments the bioactive agent is one or more biologics selected from ADAMTS13, Albumin (Human), Alpha‐1‐Proteinase Inhibitor (Human), Standardized Cat Hair allergen, standardized Cat Pelt allergen, Anthrax Immune Globulin (Human), Anthrax Vaccine Adsorbed, Adjuvanted, Anti‐Human Globulin, Anti‐thymocyte Globulin, Antibody to Hepatitis B Surface Antigen, Antihemophilic Factor (Human), Antihemophilic Factor (Recombinant), Antihemophilic Factor (Recombinant), Fc Fusion protein, Antihemophilic Factor (Recombinant), Full Length, Antihemophilic Factor (Recombinant), GlycoPEGylated‐exei, Antihemophilic Factor (Recombinant), PEGylated, Antihemophilic Factor (Recombinant), Plasma/Albumin Free, Antihemophilic Factor (Recombinant), Plasma/Albumin Free, Antihemophilic Factor (Recombinant), Single Chain, Antihemophilic Factor Concentrate (Recombinant), Antihemophilic Factor/von Willebrand Factor Complex (Human), Antihemophilic factor (recombinant), PEGylated‐ aucl, Antithrombin III (Human)\, Antivenin (Latrodectus mactans), Antivenin (Micrurus fulvius), BCG Vaccine, Botulism Immune Globulin (Human), C1 Esterase Inhibitor (Recombinant), C1 Esterase Inhibitor Subcutaneous (Human), COVID‐19 Vaccine, mRNA, Coagulation Factor IX (Human), Coagulation Factor IX (Recombinant), Coagulation Factor IX (Recombinant), Albumin Fusion Protein, Coagulation Factor IX (Recombinant), Fc Fusion Protein, Coagulation Factor IX (Recombinant), GlycoPEGylated, Coagulation Factor VIIa (Recombinant), Coagulation Factor X (Human), Coagulation Factor XIII A‐Subunit (Recombinant), Coagulation Factor Xa (Recombinant), Inactivated‐zhzo, Cytomegalovirus Immune Globulin Intravenous (Human), Digoxin Immune Fab, Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed, Diphtheria & Tetanus Toxoids Adsorbed, Diphtheria Toxoid Concentrate, Factor IX Complex, Factor XIII Concentrate (Human), Fibrin Sealant (Human), Fibrinogen (Human), Fibrinogen Concentrate (Human), Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate), Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate), Hemin, Hepatitis A & Hepatitis B (Recombinant) Vaccine, Hepatitis A Vaccine, Hepatitis B Immune Globulin (Human), Hepatitis B Vaccine (Recombinant), Hepatitis B Vaccine (Recombinant), Adjuvanted, Hepatitis B Virus Core Antigen (E.coli, Recombinant), Human T‐Lymphotropic Virus Types I and II (E coli, Recombinant) Antigen and Synthetic Peptides, Hepatitis C Virus (E coli, Recombinant) NS3 Helicase Antigens and Synthetic Core Peptide, Hepatitis C Virus Encoded Antigens (Recombinant c100‐3, HCr43), Hepatitis C Virus Encoded Antigens (Recombinant c100‐3, HCr43, NS5) 0043, House Dust Mites (Dermatophagoides farinae and Dermatophagoides pteronyssinus) Allergen Extract, Human Papillomavirus 9‐valent Vaccine, Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Human Papillomavirus Quadrivalent (Types 6, 11, 16 and 18) Vaccine, Immune Globulin (Human), Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, Influenza Vaccine, Influenza Virus Vaccine, H5N1, Japanese Encephalitis Vaccine, Inactivated, Adsorbed, Meningococcal (Groups A, C, Y and W‐135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine, Meningococcal (Groups A, C, Y, W) Conjugate Vaccine, Meningococcal (Groups A, C, Y, and W‐135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine, Meningococcal Group B Vaccine, Meningococcal Groups A, B, C, W and Y Vaccine, Pathogen Reduced Cryoprecipitated Fibrinogen Complex (PRCFC), Plasma Cryoprecipitate, Plasma Protein Fraction (Human), Pneumococcal 13‐valent Conjugate Vaccine (Diphtheria CRM197 Protein), Pneumococcal 15‐valent Conjugate Vaccine, Pneumococcal 20‐valent Conjugate Vaccine, Pneumococcal Vaccine, Polyvalent, Pollens ‐ Grasses, Bermuda Grass Cynodon dactylon, Pollens ‐ Grasses, Bluegrass, Kentucky (June) Poa pratensis, Pollens ‐ Grasses, Fescue, Meadow Festuca elatior, Pollens ‐ Grasses, Orchard Grass Dactylis glomerata, Pollens ‐ Grasses, Redtop Agrostis alba, Pollens ‐ Grasses, Ryegrass, Perennial Lolium perenne, Pollens ‐ Grasses, Sweet Vernal Grass Anthoxanthum odoratum, Pollens ‐ Grasses, Timothy Phleum pratense, Pollens ‐ Weeds and Garden Plants, Ragweed, Short Ambrosia artemisiifolia, Pollens ‐ Weeds and Garden Plants, Ragweed, Short Ambrosia elatior, Protein C Concentrate (Human), Prothrombin Complex Concentrate (Human), Prothrombin complex concentrate, human‐lans, Rabies Immune Globulin (Human), Rabies Vaccine, Rabies Vaccine Adsorbed, Respiratory Syncytial Virus Vaccine, Adjuvanted , Respiratory Syncytial Virus Vaccine, mRNA, Rho(D) Immune Globulin (Human), Short Ragweed Pollen Allergen Extract, Mixed Pollens Allergen Extract, Talimogene laherparepvec, Tetanus Immune Globulin (Human), Tetanus Toxoid Concentrate, Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed, Tetanus and Diphtheria Toxoids, Thrombin (Recombinant), Thrombin (Human), Tick‐Borne Encephalitis Vaccine, Timothy Grass Pollen Allergen Extract, Trypanosoma cruzi (E. coli, Recombinant) Antigen, Trypanosoma cruzi (T. cruzi) Whole Cell Lysate Antigen, Tuberculin, Purified Protein Derivative, Typhoid Vi Polysaccharide Vaccine, Vaccinia Immune Globulin, Varicella Zoster Immune Globulin (Human), Honey Bee Venom, Mixed Vespid Venom Protein, Wasp Venom Protein, Venom Protein, Yellow Hornet Venom Protein, Yellow Jacket Venom Protein, Voretigene Neparvovec, Yellow Fever Vaccine, Zoster Vaccine Recombinant, Adjuvanted, antihemophilic factor (recombinant), Fc‐VWF‐XTEN fusion protein‐ehtl, beremagene geperpavec‐svdt, delandistrogene moxeparvovec‐rokl, etranacogene dezaparvovec‐drlb, fidanacogene elaparvovec‐dzxt, immune globulin intravenous, human‐stwk, nadofaragene firadenovec‐vncg, onasemnogene abeparvovec‐xioi, plasminogen, human‐tvmh, valoctocogene roxaparvovec‐rvox, von Willebrand Factor/Coagulation Factor VIII Complex (Human), or von Willebrand factor (Recombinant). In some embodiments, the bioactive agent is selected from one or more of Abciximab (Reopro), Rituximab (MabThera, Rituxan), Basiliximab (Simulect), Daclizumab (Zenapax),,Etanercept (TNFR2 ECD, 1998), Alefacept (LFA3 ECD, 2003), Abatacept (CTLA4 ECD, 2005) , Rilonacept (IL-1RI/IL-1RacP ECD, 2008), Romiplostim (41aa thrombopoietin (TPO) analogue peptide, 2008), Belatacept (CTLA4 ECD, 2011), Insulin, Pramlintide acetate, Growth hormone GH, Pegvisoman, Mecasermin, Factor VIII, Factor IX, Protein C concentrate, α1-proteinase inhibitor, Erythropoietin, Filgrastim, Sargramostim , Oprelvekin, Human follicle-stimulating hormone (FSH), Human chorionic gonadotropin (HCG), Lutropin-α, Denileukin diftitox, Interferon alfacon 1, Interferon-α2a (IFNα2a), Interferon-α2b (IFNα2b), Interferon-αn3 (IFNαn3), Interferon-β1a (rIFN-β), Interferon-β1b (rIFN-β), Interferon-γ1b (IFNγ), Salmon calcitonin, Teriparatide, Exenatide, Octreotide, Dibotermin-α, Recombinant human bone morphogenic protein 7, Histrelin acetate, Palifermin, Becaplermin, Nesiritide, Lepirudin, Anakinra, Enfuvirtide, β- Glucocerebrosidase, Alglucosidase-α -, Laronidase -, Idursulfase, Galsulfase, Agalsidase- β, Lactase, Adenosine deaminase, Tissue plasminogen activator (tPA), Drotrecogin-α -, Trypsin, Botulinum toxin type A, Botulinum toxin type B, Collagenase, Human deoxyribonuclease I, Hyaluronidase, Papain, or L-Asparaginase. In some embodiments, the bioactive agent is one or more nucleic acids, such as an oligonucleotide or modified oligonucleotide that is long acting or resistant to nucleases. In some embodiments, the nucleic acid bioactive agent is selected from one or more of fomivirsen, mipomersen, inotersen, eteplirsen, golodirsen, nusinersen, patisiran, givosiran or pegaptanib. See, e.g., Roberts, T.C., Langer, R. & Wood, M.J.A. Advances in oligonucleotide drug delivery. Nat Rev Drug Discov 19, 673–694 (2020).In some embodiments, the bioactive agent is a GLP-1 agonist. In some embodiments, the GLP-1 agonist is selected from one or more of tirzepatide. dulaglutide, exenatide, semaglutide, liraglutide, or lixisenatide. In some embodiments, the bioactive agent is selected from one or more agents that can be useful for treating cancer in a subject, comprising Cetuximab, Leuprolide, Pegfilgrastim, Sargramostim, Thyrotropin Alfa, Trastuzumab, Capromab, Filgrastim, Bevacizumab, Pertuzumab, Denosumab, Buserelin, Aflibercept, Abarelix Satumomab Pendetide, Ancestim, Filgrastim-sndz, Pembrolizumab, Necitumumab, Sipuleucel-T, Capromab pendetide, Galiximab, Ranpirnase, Oregovomab, LErafAON, M40403, Tigapotide, IGN311, Adecatumumab, Labetuzumab, Matuzumab, Bavituximab, Keyhole limpet hemocyanin, Girentuximab, Cintredekin besudotox, Oportuzumab monatox, INGN 201, INGN 225, NAV 1800, AVN-944, Cantuzumab ravtansine, Farletuzumab, IRX-2, Trastuzumab emtansine, CT-011, Leronlimab, IMC-1C11, Nimotuzumab, Endostatin, Sibrotuzumab, Bivatuzumab, Lexatumumab, Volociximab, Durvalumab, Stem bromelain, Moxetumomab pasudotox, Sacituzumab govitecan, Enfortumab vedotin, Trastuzumab deruxtecan, Dostarlimab, Amivantamab, Tisotumab vedotin, NV1020, CG7870, ZYC300, VPM4001, IGN301, 1D09C3, SOT-107, VB2-011, IDD-1, SGN-30, ADH-1, LM-609, TA-CIN, GnRH pharmaccine, SGN-15, G207, 99mTc-14 F7 Mab, anti-alpha5Beta1- integrin antibody, TRC093, Mitumomab, or rNAPc2. In some embodiments, the bioactive agent for treating cancer is selected from the group consisting of Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Adrucil (Fluorouracil), Afatinib Dimaleate, Afinitor (Everolimus), Aldara (Imiquimod), Aldesleukin, Alemtuzumab, Alimta (Pemetrexed Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi, Avastin (Bevacizumab), Axitinib, Azacitidine, BEACOPP, Becenum (Carmustine), Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar (Tositumomab and I 131 Iodine Tositumomab), Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cabozantinib-S-Malate, CAF, Campath (Alemtuzumab), Camptosar (Irinotecan Hydrochloride), Capecitabine, CAPOX, Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implant, Casodex (Bicalutamide), CeeNU (Lomustine) Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cometriq (Cabozantinib-S-Malate), COPP, COPP-ABV, Cosmegen (Dactinomycin), Crizotinib, CVP, Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine, Liposomal, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin, Dasatinib, Daunorubicin Hydrochloride, Decitabine, Degarelix, Denileukin Diftitox, Denosumab, DepoCyt (Liposomal Cytarabine), DepoFoam (Liposomal Cytarabine), Dexrazoxane Hydrochloride, Docetaxel, Doxil (Doxorubicin Hydrochloride Liposome), Doxorubicin Hydrochloride, Doxorubicin Hydrochloride Liposome, Dox-SL (Doxorubicin Hydrochloride Liposome), DTIC-Dome (Dacarbazine), Efudex (Fluorouracil), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Eloxatin (Oxaliplatin), Eltrombopag Olamine, Emend (Aprepitant), Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi), Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Evacet (Doxorubicin Hydrochloride Liposome), Everolimus, Evista (Raloxifene Hydrochloride), Exemestane, Fareston (Toremifene), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil), Fluorouracil, Folex (Methotrexate), Folex PFS (Methotrexate), FOLFIRI, FOLFIRI- BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonavalent Vaccine), Gazyva (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE- OXALIPLATIN, Gemtuzumab Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Herceptin (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan Hydrochloride), Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Ifex (Ifosfamide), Ifosfamide, Ifosfamidum (Ifosfamide), Imatinib Mesylate, Imbruvica (Ibrutinib), Imiquimod, Inlyta (Axitinib), Intron A (Recombinant Interferon Alfa-2b), Iodine 131 Tositumomab and Tositumomab, Ipilimumab, Iressa (Gefitinib), Irinotecan Hydrochloride, Istodax (Romidepsin), Ixabepilone, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana (Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifene (Raloxifene Hydrochloride), Kepivance (Palifermin), Keytruda (Pembrolizumab), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposome), Liposomal Cytarabine, Lomustine, Lupron (Leuprolide Acetate), Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Lupron Depot-3 Month (Leuprolide Acetate), Lupron Depot-4 Month (Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megace (Megestrol Acetate), Megestrol Acetate, Mekinist (Trametinib), Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ (Methotrexate), Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride), Mutamycin (Mitomycin C), Myleran (Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Navelbine (Vinorelbine Tartrate), Nelarabine, Neosar (Cyclophosphamide), Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate), Nilotinib, Nivolumab, Nolvadex (Tamoxifen Citrate), Nplate (Romiplostim), Obinutuzumab, OEPA, Ofatumumab, OFF, Olaparib, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ontak (Denileukin Diftitox), Opdivo (Nivolumab), OPPA, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Pamidronate Disodium, Panitumumab, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib Hydrochloride, Pegaspargase, Peginterferon Alfa-2b, PEG-Intron (Peginterferon Alfa-2b), Pembrolizumab, Pemetrexed Disodium, Perjeta (Pertuzumab), Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopag Olamine), Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, R-EPOCH, Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), Rituximab, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Ruxolitinib Phosphate, Sclerosol Intrapleural Aerosol (Talc), Siltuximab, Sipuleucel-T, Somatuline Depot (Lanreotide Acetate), Sorafenib Tosylate, Sprycel (Dasatinib), STANFORD V, Sterile Talc Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib), Sunitinib Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon Alfa-2b), Sylvant (Siltuximab), Synovir (Thalidomide), Synribo (Omacetaxine Mepesuccinate), TAC, Tafinlar (Dabrafenib), Talc, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib),Taxol (Paclitaxel),Taxotere (Docetaxel), Temodar (Temozolomide), Temozolomide, Temsirolimus, Thalidomide, Thalomid (Thalidomide), Thiotepa, Toposar (Etoposide), Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Tositumomab and I 131 Iodine Tositumomab, Totect (Dexrazoxane Hydrochloride), TPF, Trametinib, Trastuzumab, Treanda (Bendamustine Hydrochloride), Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Vandetanib, VAMP, Vectibix (Panitumumab), VeIP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, VePesid (Etoposide), Viadur (Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate, Vincasar PFS (Vincristine Sulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Hydrochloride), Wellcovorin (Leucovorin Calcium), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRI, Xgeva (Denosumab), Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide), Yervoy (Ipilimumab), Zaltrap (Ziv-Aflibercept), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zinecard (Dexrazoxane Hydrochloride), Ziv-Aflibercept, Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), and Zytiga (Abiraterone Acetate). In some embodiments, the bioactive agent is selected from one or more immune checkpoint inhibitors, e.g., useful for treating cancer in a subject. In some embodiments, the agent is selected from one or more of ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, durvalumab, or tiragolumab. In some embodiment, the bioactive agent is an antibody. In some embodiments, the bioactive agent is an antibody-drug conjugate. In some embodiments, the bioactive agent is any of the antibodies as provided herein conjugated with any of the bioactive agent drugs (e.g., chemotherapeutic drugs) as provided herein. In some embodiments, the bioactive agent comprises one or more agents that can be useful for treating infectious disease in a subject, including Gramicidin D, Interferon Alfa-2a, Recombinant, Daptomycin, Filgrastim, Teicoplanin, Filgrastim-sndz, Tuberculin Purified Protein Derivative, Obiltoxaximab, Hepatitis A Vaccine, Human Varicella-Zoster Immune Globulin, Lenograstim, Erythropoietin, Interferon alfa-2a, Bavituximab, Ciliary neurotrophic factor, QS-21, CPG 10101, PRO-542, Motavizumab, Ibalizumab, Bezlotoxumab, Besilesomab, Elapegademase, Atoltivimab, Maftivimab, Odesivimab, Imdevimab, Casirivimab, P113D, LC16M8, MVA3000, VIR201, KB001, rhMBL, PI- 0824, HGTV-43, CCR5 mAb, MDX-1303, Bulevirtide, and Bebtelovimab. In some embodiments, the bioactive agent comprises one or more agents that can be useful for treating an immunological disorder in a subject, including immunoglobulin, Alefacept, Daratumumab, Immune Globulin Human, Vedolizumab, Siltuximab, Dinutuximab, Sipuleucel-T, Human immunoglobulin G, Somatotropin, Caplacizumab, Bovine type I collagen, Rabies immune globulin, human, Inebilizumab, Ibalizumab, Pepsin, Elapegademase, Belantamab mafodotin, Cilgavimab, Tixagevimab, and rhMBL In some embodiments, the bioactive agent comprises one or more agents that can be useful for treating a cardiac disorder in a subject, including Abciximab, Erythropoietin, Pexelizumab, Coagulation factor VII human, FX06, ACY001 In some embodiments, the bioactive agent comprises one or more agents that can be useful for treating a hormonal disorder in a subject, including Pegvisomant, Buserelin, Tesamorelin, Thyroglobulin, Sipuleucel-T, Somatotropin, Tigapotide, Corifollitropin alfa, Somatrem, Mecasermin rinfabate, Somatrogon, and Somapacitan In some embodiments, the bioactive agent comprises one or more agents that can be useful for treating a neurological disorder in a subject, including Immunoglobulin, Sulodexide, Immune Globulin Human, Dinutuximab, Human immunoglobulin G, Inebilizumab, Cerliponase alfa, Cenegermin, Satralizumab, Naxitamab, and Equine Botulinum Neurotoxin E Immune FAB2 In some embodiments, the bioactive agent comprises one or more agents that can be useful in adjunct therapy in a subject, including Dornase alfa, Insulin Regular, Insulin Lispro, Abciximab, Infliximab, Exenatide, Pramlintide, Insulin aspart, Golimumab, Golimumab, Belimumab, Albiglutide, Alirocumab, Dulaglutide, Hyaluronidase (Human Recombinant), Ramucirumab, Metreleptin, Caplacizumab, Thrombin alfa, Tasonermin, Dibotermin alfa, Dibotermin alfa, Besilesomab, Evinacumab, and Tirzepatide In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a genetic disorder in a subject, including Somatotropin, Talimogene laherparepvec, and Elapegademase. In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a respiratory disorder in a subject, including Palivizumab, Lucinactant, Beractant, Beractant, Poractant alfa, and Albumin human. In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a hematological disorder in a subject, including Emapalumab and Tagraxofusp. In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating an eye disorder in a subject, including Gramicidin D, Botulinum Toxin Type A, Ciliary neurotrophic factor, Teprotumumab, and Teprotumumab In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a bone disorder in a subject, including Burosumab. In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a metabolic disorder in a subject, including Insulin detemir. In some embodiments, the bioactive agent comprises one or more agents that can be useful in treating a malabsorption disorder in a subject, including Teduglutide. In some embodiments, the bioactive agent comprises a system for achieving genomic modification in cells, such as a CRISPR/Cas9 system. In some embodiments, one or more targeted "nucleases," e.g. CRIPSR/Cas9, TALEN or ZFN, can create a double-stranded break in the target sequence (e.g., cellular chromatin) at a predetermined site. A "target site" or "target sequence" is a nucleic acid sequence that defines a general region of a nucleic acid to which a binding molecule may bind, provided sufficient conditions for binding exist. In some embodiments, the CRISPR/Cas system comprises (a) a gRNA molecule comprising a targeting domain which is complementary with a target domain sequence of a gene of interest; (b) a Cas9 molecule or variant thereof, or nucleic acid encoding the same; and (c) optionally a template nucleic acid sequence that harbors the desired genomic modification. In some embodiments the bioactive agent is a vitamin or a micronutrient. Preferred vitamins or micronutrients include, without limitation, vitamin C, vitamin E, vitamin B12, vitamin B6, folic acid, beta carotene and niacin or combinations thereof. A combination of vitamin C and vitamin E is one preferred embodiment. One embodiment may further include niacin. Niacin in combination with an anti-inflammatory agent is another preferred embodiment. Preferred anti-inflammatory agents include, without limitation, corticosteroid medicines such as cortisone, hydrocortisone, prednisone and methylprednisolone and non- steroidal anti-inflammatories (NSAIDs) wherein the NSAID is selected from the group consisting of aspirin (acetylsalicylic acid), diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen and naproxen sodium, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, celecoxib and acetaminophen, provided, however, that when the NSAID is aspirin, ibuprofen, acetaminophen, or a cox-2 inhibitor, the formulation does not include micronized niacin. In some embodiments the bioactive agent is an antimicrobial or antiviral antibiotic. Preferred antimicrobial antibiotics include antibacterial antibiotics antiparasitic antibiotics and antifungal antibiotics. Preferred fungicides include, without limitation, butocouazole nitrate, haloprogen, clotrimazole and other azoles. Preferred antivirals include, without limitation, O-[(2-hydroxyetoxy)- methyl]guanine and other herpes treatment medications, and tee tree oil (oil of Melaleuca spp.). In some embodiments the bioactive agent is an antioxidant selected from, without limitation, urocanic acid and other imidazoles; D,L-carnosine, D-carnosine, L-carnosine, anscrine and other peptides; alpha-carotine, beta-carotine, lycopine and other carotines; carotenoids; dihydrolipoic acid and other lipoic acids; aurothioglucose, propylthiouracil, thioredoxin, glutathion, cysteine, cystine, cystamine and other thiols; dilauryl thioproponate; distearyl thiopropionate; thiopropionate; thiopropionic acid; butathione- sulfoxamines, homocysteine-sulphoxamine, butathione-sulphones, penta-, hexa- and heptathioninesulphomimine and other sulfoxamine compounds; alpha-hydroxy-fatty acids, palmitic acid, lactoferrin, EDTA, EGTA and other metal chelating agents; citric acid, lactic acid, malic acid and other alpha-hydroxy acids; gamma-linolenic acid, linoleic acid, oleic acid and other unsaturated fatty acids; folic acid; ubiquinone, ubiqinol and other quinones; vitamin C; ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate and other vitamin C derivatives; vitamin E acetate and other tocopherols and tocopherol derivatives; retinoids; vitamin A; vitamin A palmitate and other vitamin A derivatives; coniferyl benzooate of benzoin resin; rutic acid; alpha-glycosylrutin; ferulic acid furfurylideneglucitol; carnosine; butylhydroxytoluene (BHT); butylhydroxyanisole (BHA); nordihydroguaic resin acid; nordihydroguaiaretic acid; trihydroxybuterophenone; uric acid; mannose; ZnO, ZnO₄ and other zinc compounds; selenium and stilbenes. In certain embodiments the bioactive agent is a sugar, an amino acid or a small peptide, including, without limitation carnosine, acetyl-L-carnithine, N-acetyl-carnithine, N-acetyl-cysteine, N-acetyl-D-glucosamine, B/D/L-alanine, alpha-keto-glutarates, arginates, L-arganine base/HCl, L-arginine-pyroglutamate, ascorbates, L-aspargine monohydrate, aspartame, aspartates, L-aspartic acid, L-carnithine base, L-carnithine fumarate, L-carnithine/HCl, L carnithine bitartrate, L-carnithine-L-tartrate, chelates, L- citruline, creatin monohydrate, creatin phosphate, creatine pyruvate, L-cysteine base, L- cysteine/HCl monohydrate, anhydrous L-cysteine/HCl, cysteinates, N,N-dimethylglycine base/HCl, glutamates, L-glutamic acid, L-glutamine, L-glutamine peptide, reduced L- glutathione, L-glycine, keto-glutaric acid, L-histidine base/HCl, L-isoleucine, L-leucine, lysinates, L-lysine monohydrate/HCl, D-mannose, DL/L-methionine, L-ornithine/HCl, DL/L-phenylalanine, L-hydroxyproline, trans-hydroxy-L-proline, pyroglutamic acid, D/L- ribose, L-selenium-methionine, L-serine, taurates, tartarates, L-threonine, trimethylglycine, DL/L-tryptophan, taurine, L-theanine, L-tyrosine, L-valine, xylitol, D- xylose, DL/L-zinc monomethionine, and all other D or L-amino acids and short peptides and all bases, acids and salts thereof. In certain embodiments the antioxidant may be an antioxidant derivative. Preferred derivatives include, without limitation, esters, ethers, peptides, lipids, nucleotides and nucleosides of such antioxidants. Preferred derivatives also include glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl lauryl, palmitoyl, oleyl, gamma-linoloyl, cholesteryl and glyceryl esters of such antioxidants. In some embodiments the bioactive agent is a biological additive. As used herein, the term “biological additive” indicates any compound obtained from a natural source, including plants, animals, bacteria and yeast, which has a medicinal or otherwise beneficial effect when topically applied to the skin. Examples of biological additives include, without limitation, oil of Melaleuca spp. (tea tree oil), oil of Lavandula angustifolia, Carica papaya extract, Echinacea angustifolia extract, Mimosa tenuiflora extract, Hydrocotyl (centella) asiatica extract, gingko biloba extract, Matricaria chamomila (chamomile oil) extract, Hypericum perforatum extract, Aloe barbedensis extract, and the like. The biological sources for “biological additive” may also include, but are not limited to the following: Aloe Vera, (e.g., Aloe Barbedensis); Arnica, (e.g., Arnica Montana); Bladderwrack (seaweed), (e.g., Fucus Vesciculosis); Birch, (e.g., Betula Alba) (Pendula); Chamomile, (e.g., Matricaria Chamomila, Chamomila Recutita); Marsh Mallow, (e.g., Althea Officinalis); Meadow Sweet, (e.g., Spirea Ulmaria) (Filipendula); Mint/Lemon Balm, (e.g., Melissa Officinalis); Mimosa, (e.g., Mimosa Tenuiflora); Myrrh Tincture, (e.g., Commiphor Myrrha); Neem, (e.g., Melia Azadirachta); Nettle (stinging), (e.g., Urtica Dioica); Papaya, (e.g., Carica Papaya); Propolis (bee glue), (e.g., Propolis Cera); Raspberry, (e.g., Rubis Idaeus); Red Poppy, (e.g., Papaver Rhoeas); Rose Hip (dog rose), (e.g., Rosa Carima); Rosemary, (e.g., Rosemarinus Officinalis); Sage, (e.g., Salvia Officinalis); St. Johns Wort, (e.g., Hypericum Perforatum); Strawberry, (e.g., Fragaria Vesca); Thea Sinensis (green tea), (e.g., Camelia Sinensis); Walnut, (e.g., Juglans Regia); Witchhazel (dist/extr), (e.g., Hamamelis Virginiana); Yarrow, (e.g., Achillea Millefolium); Wild Yam, (e.g., Dioscorea Villosa); Hawthorn, (e.g., Crataegus Monogina/Oxyantha); Herma (black/rod), (e.g., Lawsoma Ehemus); Hops, (e.g., Humulus Lupulus); Horse Chestnut, (e.g., Aesculus Hippocastanum); Horse Tail, (e.g., Equisitum Arvense); Ivy, (e.g., Hedera Helix); Linden/Lime Tree Blossoms, (e.g., Tilia Argentea Cordata); Madder, (e.g., Rubia Tinctorum); Marigold, (e.g., Calendula Officinalis, Centella Asiatica, Centella Asiatica Urban, Hydrocotyl Asiatica); Carrot (roots), (e.g., Daucus Carota); Comfrey (Allantoine), (e.g., Symphytum Officinale); Coneflower (Echinacea), propolis (e.g., Echinacea Angustifolia); Cucumber, (e.g., Cucumis Sativus, Frucus Cucumis); Fenugreek, (e.g., Trigonella Foenum Greacum); Gingko, (e.g., Gingko Biloba); Ginseng, (e.g., Panax Ginseng); Great Burdock, (e.g., Radix Bardanea/Arctium Lappa); Tea Tree Oil, (e.g., Oil of Melaleuca Alternifolia); Colts Foot, (e.g., Tussilago Farfara); Clover, arbutui (e.g., Trifolium Pratense); Speedwell, (e.g., Veronica Officinalis). A particularly preferred biological additive is tea tree oil. In a preferred embodiment, one or more biological additive is present in the formulation in a combined amount of from about 1% to 10% by weight, more preferably from about 2% to 8% by weight, and most preferably from about 4% to 6% by weight. In some embodiments the bioactive agent is a local anesthetic. Preferred local anesthetics include, without limitation, lidocaine and procaine. See also Martindale, The Extra Pharmacopia, Twenty-eighth Edition, The Pharmaceutical Press, London (1982), pp. 899-923. In some embodiments, the total dose of the bioactive agents that can be administered to a subject (in single or in divided doses) can be in amounts, for example, from 0.01 to 25 mg/kg body weight, or more usually from 0.1 to 15 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In some embodiments, treatment regimens according to the present invention comprise administration to a human or other mammal in need of such treatment from about 1 mg to about 1000 mg of the bioactive substance(s) or in a single dose of from 1 mg, 5 mg, 10 mg, 100 mg, 500 mg or 1000 mg. The compositions can be administered once, twice, or multiple times. In some embodiments, the compositions are administered, daily, weekly, monthly, every few months, or as needed or prescribed. In some embodiments, the composition comprising the bioactive agent useful for treating a disease or condition is administered alone. In some embodiments, the composition is administered in combination with one or more additional therapies, either together in the same composition, in separate compositions with the same or different routes of administration, either at the same time or at different times. For example, in some embodiments, bioactive agents useful for treating cancer, such as one or more checkpoint inhibitors are administered in combination with one or more chemotherapeutic agents. In some embodiments, the bioactive agent is poorly soluble or generally insoluble. In some embodiments, the bioactive agent has a particle size at the nanoscale level to increase the rate of dissolution of poorly soluble drugs and increase percutaneous absorption of insoluble drugs by enlarging the effective surface area. In some embodiments, the composition comprises an exfoliant. For purposes of the invention, an “exfoliant” is a substance that eliminates dead cells from the stratum corneum without killing underlying living skin cells. In certain embodiments the exfoliants are chemical exfoliants, such as alpha hydroxy acids (AHAs) and beta hydroxy acids (BHAs). In certain embodiments, the exfoliating agents are enzymes . Preferred enzymes include, without limitation, serine proteases, macramidase, penicillinase, pepsin, plasmin, bromelain, papain, streptokinase, sutilains, trypsin, urokinase, keratinase, amylase, hyaluronidase, cholic acid, chymopapain, chymotrypsin, cynara, brinolase and chenodeoxycholic acid. See also Martindale, The Extra Pharmacopia, Twenty-eighth Edition, The Pharmaceutical Press, London (1982), pp. 644-661. In some embodiments, the composition comprises an amino acid derivative compound as a permeation enhancer. In some embodiments, the amino acid derivatives comprise a hydrophobic “tail” attached to an amino acid “head” via a biodegradable linkage, e.g., an ester bond. In some embodiments, an amphiphilic enhancer is incorporated into the stratum corneum lipid barrier and disrupts the tight arrangement of the membrane lipids. In some embodiments, after reaching the enzymatically active nucleated epidermis, its labile bond is hydrolyzed. Acyclic amino acid-based permeation enhancers include derivatives of glycine (e.g., dodecyl-N,N-dimethylamino acetate (DDAA)), alanine (e.g., dodecyl-2-(dimethylamino)propionate (DDAIP)), sarcosine (e.g., lauroylsarcosine), proline (e.g., dodecyl-N-acetylprolinate (e.g., L-Pro2)), and 6- aminohexanoates (e.g., transkarbam 12 (T12) and undecyl 6-(dimethylamino)hexanoate (DDAK)). See, e.g., Pereira, et al., Current status of amino acid-based permeation enhancers in transdermal drug delivery, Membranes 2021, 11: 343, which is incorporated by reference in its entirety. In some embodiments, amino acid derivative skin permeation enhancers can take the following form: (AA) ---- (L) ---- (HP), wherein AA is an amino acid or a group of two amino acid molecules linked together by a peptide bond or an alkylene chain linking group having up to six carbon atoms, wherein L is a linker group, and wherein HP is a hydrophobic moiety. The makeup of the HP portion is not particularly limiting and can be any moiety having substantial hydrophobic character. HP can be a branched or unbranched alkyl or alkenyl hydrocarbon chain. The alkyl or alkenyl hydrocarbon chain can have 10 to 20 carbon atoms. Advantageously, HP can be an unbranched alkyl chain having 10-12 carbon atoms or an unbranched alkenyl chain having 18-20 carbon atoms. The function of the linker group L is to tie the hydrophilic “head group,” here represented by an amino acid moiety, to the hydrophobic “tail” to form an amphiphilic skin permeation enhancer. The constitution of linker group L is not particularly limiting. Advantageously, linker group L can be an ester or amide group. An ester linking group L is especially useful because it can readily be hydrolyzed after delivery of a drug into products that are less toxic than the enhancer molecule, where removal of the enhancer assists with return of the skin to its natural permeability. In particular embodiments, the linker group L can be a single bond, a carbonyl group, -C(O)-O-CH2, -C(O)-O-CH2CH2-, -C(O)-NH-CH2- and –C(O)-NH-CH2CH2-. The AA moiety can comprise any natural amino acid or any of a variety of artificial amino acids. The amino acids can be natural L-amino acids or D-amino acids or a combination thereof. For example, the AA moiety can be an amino acid molecule or a group of two amino acid molecules linked together by a peptide bond, wherein the amino acid molecules are selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, 6- (dimethylamino)hexanoic acid and derivatives thereof. Amino acids can be derivatized, for example, by alkyl groups including methyl, ethyl, n-propyl, or isopropyl, by alkoxy groups including methoxy or ethoxy, or by other substituent groups including hydroxy, amino, or alkylamino such as methylamino. In some embodiments, the amino acid derivative is selected from a compound identified in Table 1, or a combination thereof. Table 1. Polar Head Amino E^nhancer Flux Rate Donor A_cid ^{Structure ER} _/µg·cm ⁻² _·h ^{−1 Drug} _Conditions ^Cytotoxicity

Polar Head Amino A_cid ^{Enhancer Structure ER} Flux Rate /_µg·cm ⁻² _·h ^{−1 Drug} Donor C_onditions ^Cytotoxicity

some a penetrating peptides (CPPs) and antimicrobial peptides (AMPs). Cell-penetrating peptides (CPPs) are generally amphiphilic peptides of up to 30 amino acids derived from natural or unnatural protein sequences, mostly composed of positively charged amino acids, like arginine and lysine. CPPs are commonly linked to the drug (cargo) through covalent or electrostatic bonds and can penetrate the SC corneocyte cells by destabilizing the intercellular matrix and increasing permeability and therefore enabling the transport of their cargoes across the skin. Compared to classic amino acid-based CPEs, peptide-based transport offers some advantages, namely the ability to transport large hydrophilic molecules like proteins, peptides, even nucleic acids, and small interfering RNA (siRNA), across the skin. CPPs can also interact with drugs in different ways, such as through non- covalent interactions in donor formulation, by conjugation with drug components through biodegradable covalent bonds. In some embodiments, the topical pharmaceutical composition comprises a cell penetrating peptide. In some embodiments, the peptides are positively charged. In some embodiments of the, at least 50% of the component amino acid residues of each peptide are either arginine or lysine. In some embodiments, at least 50% of the component amino acid moieties of each peptide can be arginine, lysine, proline, or histidine. In some embodiments, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% at least 80%, at least 90%, or 100% of the amino acid residues of each cell penetrating peptides is either arginine, lysine, or proline. In some embodiments, the cell penetrating peptide can be a homopolymer of arginine, lysine or ornithine. See, e.g., R.E. Taylor, et al., Cell penetrating peptides, novel vectors for gene therapy, Pharmaceutics 2020, 12: 225; I. Szabo, et al., Redesigning of cell-penetrating peptides to improve their efficacy as a drug delivery system, Pharmaceutics 2022, 14: 907, which are incorporated by reference in their entireties. The size is not necessarily limiting, but in some embodiments, the peptide consists of six to twenty amino acid residues. In some embodiments, the peptides comprise up to 30 amino acid moieties derived from natural or unnatural sequences. In some embodiments, at least 50% of the amino acid residues of each peptide are positively charged at physiological pH. In some embodiments, the positively charged amino acid residues are selected from arginine and lysine. In some embodiments the cell penetrating peptide is covalently attached to the bioactive agent, e.g., a fusion protein. In some embodiments the cell penetrating peptide is non-covalently associated with the bioactive agent. Cell penetrating peptides include protein transduction domains (PTDs) that are short modular motifs, which, when attached to heterologous proteins, can transfer proteins across cell membranes. These short motifs, generally rich in positively charged amino acids, permit transfer of proteins across plasma membrane, without requiring any receptors for their internalization. Viral and cellular proteins- such as the HIV-TAT, herpes simplex viral VP22, the homeodomain protein antennapedia, lactoferrin and fibroblast growth factor contain such domains, which can be modularly attached to other proteins. PTDs are also called cell delivery domain or cell transduction domains. The cell penetrating peptide sequence is not limiting, provided it encodes a peptide sequence that enhances uptake of a functional polypeptide by cells. In some embodiments, the cell penetrating peptide comprises RRRRRRRRRPSASYPYDVPDYA (SEQ ID NO:1). In some embodiments, the cell penetrating peptide comprises one or more variants of TAT protein from HIV selected from GRKKRRQRRR (SEQ ID NO: 2), YGRKKRRQRRR (SEQ ID NO: 1), or GRKKRRQ (SEQ ID NO: 4). Alternate forms of TAT can also be used. Non-limiting examples of cell penetrating peptides which can be used in the present invention are shown in Table 2. Table 2. Cell penetrating peptides SEQ ID NO:

RQLRIAGRRLRGRSR 16

INLKALAALAKKIL 39

In some embodiments, a linker may be used to connect one or more cell penetrating peptides and the bioactive agent. In some embodiments, the cell penetrating peptides is fused or linked in frame to the N-terminal and/or C-terminal end of any one of the bioactive agents. In some embodiments, the bioactive agent sequence is located downstream from the cell penetrating peptide sequence, i.e., the cell penetrating peptides sequence is N- terminal to the bioactive agent sequence. In some embodiments, the permeation enhancer is an antimicrobial peptide. B.H. Gan, et al., The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions, Chemical Society Reviews 2021(13). Zhang, et al., report that 3791 antimicrobial peptides are known and that they come from six kingdoms including bacteria, archaea, protozoal, fungal, plants and animals. Zhang, et al., Antimicrobial peptides: mechanism of action, activity and clinical potential, Military Med. Res.2021, 8: 48, p.1, col.1. According to Zhang, et al., most antimicrobial peptides have a net charge of +2 to +9 and include 10 to 100 amino acid moieties (p. 3, col. 1, last paragraph). Positively charged antimicrobial peptides differentially target bacterial cell membranes because they include several negatively charged materials, while mammalian cell membranes include materials having a neutral charge instead (p. 4, col. 2, last paragraph, running onto p. 5, col. 1). Cancer cells can exhibit negatively charged cell membranes as compared with normal cells, giving antimicrobial peptides a role in cancer research. One group of positively charged antimicrobial peptides, known as cathelicidins, are amphiphilic by virtue of including at least 50% hydrophobic amino acids and are α- helical. Among the cathelicidins are the magainins. In certain embodiments, the antimicrobial peptide can be magainin 2, an α-helical peptide isolated from the African clawed frog Xenopus laevis. Magainin 2 (GIGKFLHSAKKFGKAFVGEIMNS) (SEQ ID NO:48) has been noted to have significantly differing effects on bacterial versus mammalian cell membranes, forming pores of differing sizes in the membranes. Y. Imura, et al., Magainin 2 in action: distinct modes of membrane permeabilization in living bacterial and mammalian cells, Biophysical Journal 2008, 95: 5757-5765. In particular embodiments, the peptide can be magainin or a derivative of magainin. In some embodiments, the derivative of magainin can be magainin substituted by a dipeptide. In some embodiments, the dipeptide derivative of magainin can be magainin substituted by Gly-Ala. In some embodiments, the dipeptide derivative of magainin can be magainin substituted by Lys-Leu. In some embodiments, the permeation enhancer is a peptide that comprises an amino acid sequence that is at least 80%, 85%, 90%, or 95% or more identical to any of SEQ ID NOS:1-49. In some embodiments, the composition comprises a lipid nanoparticle composition. In some embodiments, the lipid nanoparticle (LNP) composition comprises one or more cationic lipids. In certain embodiments, the diameters of the lipid nanoparticles can be within a range of from about 10 nm to about 60 nm. In some embodiments, the nanoparticles can facilitate sustained drug release for a long period of time. In some embodiments, the nanoparticles can protect encapsulated materials from chemical degradation. The nanoparticles can be prepared from natural or synthetic polymers. In embodiments, the lipid nanoparticles can comprise chitosan. In some embodiments, the lipid nanoparticles can comprise synthetic polymers including polyalkylcyanoacylates, poly-lactic acid, poly-caprolactone, poly-glycolic acid, or their copolymers, e.g., poly- lactic-co-glycolic acid. See, e.g., Desai, et al., Interaction of nanoparticles and cell- penetrating peptides with skin for transdermal drug delivery, Mol. Membr. Biol. 2010, 27(7): 247-259, which is incorporated herein by reference. In some embodiments, the LNPs comprise a cationic lipid. In some embodiments, an LNP composition further comprises a helper lipid that contributes to their stability and delivery efficiency. Helper lipids with cone-shape geometry favoring the formation hexagonal II phase, such as dioleoylphosphatidylethanolamine (DOPE), can promote endosomal release. Meanwhile, cylindrical-shaped lipid phosphatidylcholine can provide greater bilayer stability, which is important for in vivo application of LNPs. Cholesterol is often included as a helper that improves intracellular delivery as well as LNP stability in vivo. Inclusion of a PEGylating lipid can enhance LNP colloidal stability in vitro and circulation time in vivo but may reduce uptake and inhibit endosomal release at the cellular level. This problem can be addressed by choosing reversible PEGylation in which the PEG moiety is gradually released in blood circulation. pH-sensitive anionic helper lipids, such as fatty acids and cholesteryl hemisuccinate (CHEMS), can trigger low-pH-induced changes in LNP surface charge and destabilization that can facilitate endosomal release. In some embodiments, the LNPs can be employed in combination with amino- based peptides for transdermal delivery of protein drugs, biologics and vaccines. In some embodiments, the LNP comprises a mixture of multiple components and excipients including ionizable lipid, helper lipid, PEG-lipid, and cholesterol. Excipients that can optionally be used in certain embodiments of the present invention, but which are not required, can include lipid nanoparticles, helper lipids, poly(ethylene glycol) lipids and cholesterol. Helper lipids can include, for example, 1,2-dioleoyl-sn-glycero-3- polyethylene (DOPE), or the O-pegylated derivative of the N,N-dimyristylamide of 2- hydroxyacetic acid (ALC-0159), available from BroadPharm, San Diego, CA. In some embodiments, the composition comprises an additional penetration enhancer, which can include, without limitation azone, urea, pyrrolidones, essential oils, terpenes and terpenoids, oxazolidinones, propylene glycol, epidermal enzymes, oleic acid, dimethyl isosorbide, sulphoxides, dimethylsulfoxide, dimethylsulfone, ethanol, diethylene glycol monoethyl ether, hyaluronic acid, chitin, mucopolysaccharides, fatty acids, linoleic acid, alpha linoleic acid, cod liver oil, menthol, menthol derivatives, squalene, glycerol derivatives, glycerol monoethers; chamomile flavones apigenin, lutrolin, and 7-O-beta- glucoside. Without wishing to be bound by theory, such penetration enhancers act through one or more of the following mechanisms: increasing the fluidity of the stratum corneum lipids and reducing the diffusional resistance to permeants; removing intercellular lipids and dialation between adherent cornified cells; increasing the thermodynamic activity of drugs in vehicles; exfoliating stratum corneum cell membranes; dissociating adherent cornified cells and elimination of the barrier function. In some embodiments, the pharmaceutical composition further comprises an effective amount of one or more vasodilators or vasoconstrictors. Vasodilators and vasoconstrictors can enable targeted drug delivery. Vasodilators act to expand or dilate the capillaries and other blood vessels in and beneath the dermal layer, resulting in increased blood flow at the site of system application. Capillary vasodilation increases the rate of diffusion of the therapeutic drug across the capillary wall and into the systemic circulation. Vasodilators that can be added include, without limitation, acetylcholine, amrinone, bamethan sulphate, bencyclane fumarate, benfurodil hemisuccinate, benzyl nicotinate, buflomedil hydrochloride, buphenine hydrochloride, butalamine hydrochloride, cetiedil citrate, ciclonicate, cinepazide maleate, cyclandelate, di-isopropylammonium dichloroacetate, ethyl nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, inositol nicotinate, isoxsuprine hydrochloride, kallidinogenase, methyl nicotinate, methyl salicylate, naftidrofuryl oxalate, nicametate citrate, niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, nicotinic acid, nicotinyl alcohol tartrate, nitric oxide, nonivamide, oxpentifylline, papaverine, papaveroline, pentifylline, peroxynitrite, pinacidil, pipratecol, propentofyltine, raubasine, suloctidil, teasuprine, thymoxamine hydrochloride, xanthinol nicotinate, diazoxide, hydralazine, minoxidil and sodium nitroprusside. Some vasodilators are centrally acting agents, including, without limitation, clonidine, quanaberz and methyl dopa. Some vasodilators are alpha-adrenoceptor blocking agents, including, without limitation, indoramin, phenoxybenzamine, phentolamine and prazosin. Some vasodilators are adrenergic neuron blocking agents, including, without limitation, bedmidine, debrisoquine and guanethidine. Some vasodilators are ACE inhibitors, including, without limitation, benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril and ramipril. Some vasodilators are ganglion-blocking agents, including, without limitation, pentolinium and trimetaphan. Some vasodilators are calcium channel blockers, including, without limitation, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine and verapamil. Some vasodilators are prostaglandins, including, without limitation, prostacyclin, thromboxane A2, L-arginine, leukotrienes, PGA, PGA1, PGA2, PGE1, PGE2, PGD, PGG and PGH. Some vasodilators are Angiotension II analogs including, without limitation, saralasin. Other vasodilators including, without limitation, nitroglycerin, labetalol, thrazide, isosorbide dinitrate, pentaerythritol tetranitrate, digitalis, and diazoxide can serve exclusively as vasodilation agents, or may also serve another function to the delivery complex such as the penetration agent or the active drug agent. One or more vasodilators or chemically modified vasodilators may be used in the delivery complex at any one time for one formulation for the purpose of transdermally delivering an active drug molecule or agent. The delivery complex may contain one or more different vasodilators in the same complex to achieve varying and different degrees and modes of vasodilation. Vasoconstrictors optimize local drug delivery and restrict systemic drug absorption as a result of intense subcutaneous vasoconstriction, as well as direct hydrostatic compression of capillaries and veins. Vasoconstrictors include, without limitation, catecholamines, norepinephrine, epinephrine, isoproterenol, dopamine, ephedrine, phenylisopropylamines, phenylephrine, amphetamine, metraminol, methoxamine, lysergic acid, lisergic acid diethylamine. The term “vasoconstrictor”, as used herein, refers to a composition of matter or mixture that narrows the lumen of blood vessels and, hence, reduces peripheral blood flow. Other examples of suitable vasoconstrictors include, without limitation, amidephrine, cafaminol, cyclopentamine, deoxyepinephrine, epinephrine, felypressin, indanazoline, metizoline, midodrine, naphazoline, nordefrin, octodrine, ornipressin, oxymethazoline, phenylephrine, phenylethanolamine, phenylpropanolamine, propylhexedrine, pseudoephedrine, tetrahydrozoline, tramazoline, tuaminoheptane, tymazoline, vasopressin, xylometazoline and mixtures thereof. In another aspect, the invention provides a method of treating a disease or condition in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition as provided herein. In some embodiments, the composition is administered to the skin and is a topical or transdermal composition. In some embodiments, effective amounts of the bioactive agent are absorbed into the subject’s blood circulation and treat the disease or condition systemically. In some embodiments, the bioactive agent acts locally in the subject’s skin. In some embodiments, the bioactive agent acts locally in the subject’s deep tissues including, without limitation, the musculoskeletal system. In some embodiments, the method further comprises exfoliating the skin of the subject prior to the administering step. In some embodiments, the administration results in a bioavailability (e.g., amount present in the systemic circulation following administration) of the bioactive agent of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared with the amount of the bioactive agent administered in the composition. In some embodiments, the composition is administered using microneedles. In some embodiments, the microneedles are arranged in an array format, and comprise a patch that contacts the skin. In some embodiments, the microneedles have a length of about 50- 1000 µm. In some embodiments, the composition is coated onto the microneedle array and administered to the skin, for passive diffusion directly into the epidermis. In some embodiments, the composition penetrates the stratum corneum, and enables further penetration into deeper skin tissues and eventually the systemic circulation. In some embodiments, the distal part of the microneedles (~25-50 µm) penetrate the stratum corneum. The disease or condition is not limiting. In some embodiments, the disease or condition is selected from a cancer, an infectious disease, an immunological disorder a cardiac or circulatory disorder, a hormonal disorder, a neurological disorder, adjunct therapy, a genetic disorder, a respiratory disorder, a hematological disorder, an eye disorder, pain, a bone disorder, a metabolic disorder, or a malabsorption disorder. In some embodiments, the disease or condition to be treated is a dermatological condition. Dermatological conditions include, without limitation, acne, bruises, burns, eczema, mycoses, pruritis, psoriasis, seborrhea, scabs, shingles, tineapedis, wounds, wrinkles and erythema of acne rosacea. Preferred agents for treating dermatological conditions include, without limitation, anti-acne preparations; anti-inflammatory agents; monobenzone and other depigmenting agents; amcinonide, diflorasone diacetate, hydrocortisone and other dermatitis relief agents; methylbenzethonium chloride and other diaper rash relief agents; mineral oil, PEG-4 dilaurate, lanolin oil, petrolatum, mineral wax and other emolients and moisturizers; alclometasone dipropionate, betamethasone valerate, isopropyl myristate MSD and other pruritic medications; anthralin, methoxsalen, coal tar and otherpsoriasis, seborrhea and scabicide agents; 2-(acetyloxy)-9-fluoro-1′,2′3′4′- tetrahydro-11-hydroxypregna-1,4-dieno[16,17b]napthalene-3,20-dione, 21-chloro-9- fluoro-1′,2′,3′,4′-terahydro-11b-hydroxypregna-1,4-dieno[16z,17b]napthalene-3,20-dione and other steroids. In some embodiments, the invention provides a method for treating a dermatologic condition, the method comprising exfoliating the skin and applying to the skin a composition comprising an anhydrous carrier medium, a bioactive agent and a permeation enhancer as described herein. The method may optionally include in the composition an exfoliant, preferably a non-irritating exfoliant. Exfoliation of the skin may be chemical, mechanical or enzymatic. Mechanical exfoliation may be carried out by any mechanical frictional force, including, without limitation, brushing, washing or particle pressure. In certain preferred embodiments, the formulation contains a wet-micronized bioactive agent. In some embodiments, the method comprises preventing the formulation according to the invention from escaping to the exterior of the skin. Preferred methods for achieving this include covering the area of the skin that has been treated with a formulation according to the invention with an occlusive patch or other occlusive agent. In some embodiments, the disease or condition to be treated is cancer. As used herein, "cancer" refers to a pathophysiological condition whereby cells are characterized by dysregulated and/or proliferative cellular growth and the ability to induce said growth, which includes but is not limited to, carcinomas and sarcomas, such as, for example, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical cancer, AIDS-related cancers, AIDS-related lymphoma, anal cancer, astrocytoma (including, for example, cerebellar and cerebral), basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor (including, for example, ependymoma, meduUoblastoma, supratentorial primitive neuroectodermal, visual pathway and hypothalamic glioma), cerebral astrocytoma/malignant glioma, breast cancer, bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor (including, for example, gastrointestinal), carcinoma of unknown primary site, central nervous system lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-Cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, Ewing's Family of tumors, extrahepatic bile duct cancer, eye cancer (including, for example, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor (including, for example, extracranial, extragonadal, ovarian), gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, squamous cell head and neck cancer, hepatocellular cancer, Hodgkin's lymphoma, hypopharyngeal cancer, islet cell carcinoma (including, for example, endocrine pancreas), Kaposi's sarcoma, laryngeal cancer, leukemia, lip cancer, liver cancer, lung cancer (including, for example, non-small cell), lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone/osteosarcoma, meduUoblastoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasia syndromes, myelodysplastic/myeloproliferative diseases, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, osteosarcoma, oropharyngeal cancer, ovarian cancer (including, for example, ovarian epithelial cancer, germ cell tumor), ovarian low malignant potential tumor, pancreatic cancer, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, prostate cancer, rectal cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, uterine sarcoma, Sezary syndrome, skin cancer (including, for example, non-melanoma or melanoma), small intestine cancer, supratentorial primitive neuroectodermal tumors, T-Cell lymphoma, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor (including, for example, gestational), unusual cancers of childhood and adulthood, urethral cancer, endometrial uterine cancer, uterine sarcoma, vaginal cancer, viral induced cancers (including, for example, HPV induced cancer), vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' Tumor, and women's cancers. In some embodiments, the pharmaceutical composition can be useful for treating or preventing a disease or condition in a subject and comprises about 20-40% (w/w) glycerin, about 5-15% (w/w), caprylic capric triglycerides (CCT), about 2-5% (w/w) salicylic acid (SA), about 2-15% (w/w) ceatearyl alcohol and polysorbate 60, about 1-6% (w/w), beeswax, about 0.1%-1% (w/w) cell penetrating peptide (cpp), about 10-30% (w/w) oleic acid (oa), about 1-5% (w/w) azone, about 5-30% (w/w) diethylene glycol monoethyl ether (degee) and about 0.1-6% (w/w) semaglitude. In some embodiments, the composition is a topical cream that is applied to the skin of the subject. In some embodiments, the pharmaceutical composition can be useful for treating metabolic disorders, diabetes or obesity in a subject. In some embodiments, the pharmaceutical composition can be useful for treating or preventing a disease or condition in a subject and comprises about 5-20% (w/w) isopropyl mysistate (ipm), about 20-40% (w/w) glycerin, about 5-15% (w/w) caprylic capric triglycerides (CCT), about 2-6% (w/w) salicylic acid (SA), about 5-10% (w/w) ceatearyl alcohol and polysorbate 60, about 1-10% (w/w) DMSO, about 0.1-6% (w/w) cell penetrating peptide (cpp), about 5-30% (w/w) oleic acid (oa), about 1-6% (w/w) terpenes, about 5-30% (w/w) diethylene glycol monoethyl ether (degee) and about 0.1-5% (w/w) mRNA. In some embodiments, the composition is a topical cream that is applied to the skin of the subject. In some embodiments, the pharmaceutical composition can be useful for generating an immune response (including a protective immune response) in a subject. In some embodiments, the pharmaceutical composition can be useful for treating or preventing a disease or condition in a subject and comprises about 1-10% (w/w) chemotherapeutic(s), about 0.25%-2% (w/w) cell penetrating peptide (cpp), about 5-40% (w/w) glycerin, about 2-30% (w/w) l-ascorbic acid, about 5-25% (w/w) caprylic capric triglycerides (CCT), about 5-30% (w/w) isopropyl mysistate (ipm), about 5-30% (w/w) diethylene glycol monoethyl ether (degee), about 2-15% (w/w) ceatearyl alcohol and polysorbate 60, about 1-6% (w/w) beeswax, about 1-6% bentone gel gtcc v, about 1-3% (w/w) salicyclic acid, about 0.25-2% (w/w) bht, about 0.50% (w/w) parabens, and about 0.50% (w/w) trihydroxystearin (thixcin r). In some embodiments, the composition is a topical cream that is applied to the skin of the subject. In some embodiments, the pharmaceutical composition can be useful for treating cancer, such as breast cancer, in a subject. In some embodiments, the pharmaceutical composition can be useful for treating or preventing a disease or condition in a subject and comprises about 5-30% (w/w) glycerin, about 5-20% (w/w) isopropyl mysistate (ipm), about 2-5% (w/w) salicyclic acid, 0.1%-1% (w/w) cell penetrating peptide (cpp), about 2-20% (w/w) oleic acid (oa), about 2-30% (w/w) diethylene glycol monoethyl ether (degee), about 1-10% (w/w) DMSO, and about 0.1-3% (w/w) monoclonal antibody. In some embodiments, the composition is applied to the skin of the subject and the antibody is absorbed into the systemic circulation. In some embodiments, the pharmaceutical composition can be useful for treating cancer in the subject. In some embodiments, the antibody is a checkpoint inhibitor antibody (e.g., as described herein). In some embodiments, the antibody is conjugated to a chemotherapeutic agent (e.g., one or more of the chemotherapeutic agents described herein). In some embodiments, the pharmaceutical composition can be useful for treating or preventing a disease or condition in a subject and comprises about 5-30% (w/w) glycerin, about 5-20% (w/w) isopropyl mysistate (ipm), about 2-5% (w/w) salicyclic acid, 0.1%-1% (w/w) cell penetrating peptide (cpp), about 2-20% (w/w) oleic acid (oa), about 2-30% (w/w) diethylene glycol monoethyl ether (degee), and about 0.1-2% (w/w) oligonucleotide (such as siRNA or antisense oligonucleotide). In some embodiments, the composition is a liquid that is useful for targeting ocular tissues and application to the eye to treat a disease or condition. All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Any discrepancy between an incorporated reference and the present description shall be resolved in favor of the present description. EXAMPLES Example 1. Transdermal delivery of Antibody FAB fragment in Rats. Currently, it is impossible to deliver therapeutic agents like small-to-medium size proteins (referred to as biologics) through the skin. However, more and more therapeutic agents are biologics aiming at reaching a single endogenous, often pathological, target. An example of such biologics are antibodies that are used more and more in daily medical practice. But, the delivery of antibodies requires skilled medical staff and the patients need to visit specialized healthcare facilities on a regular basis for injection or infusion of these antibodies into the bloodstream via venipuncture. These procedures are expensive, time-consuming, and uncomfortable for the patients. Thus, developing alternate delivery methods that would be cheaper and could be done by patients themselves in their own dwellings would greatly facilitate the large-scale applicability of antibody treatments and other biologics, hence increase access to healthcare to a larger population that does not have specialized staff and facilities in their communities. In the present Example, antibodies will be incorporated in a transdermal vehicle cream for delivery into the bloodstream. There are challenges associated with this delivery method that relate to the anatomy of the skin. As shown on Figure 1, a therapeutic agent needs to cross multiple anatomical barriers before reaching blood vessels to allow systemic delivery to organs and tissues. The first barrier is the stratum corneum, which is hydrophobic, thus requires specific drug delivery methods to go through and reach the epidermis. At the bottom of the epidermis is a thick basement membrane that is also a strong barrier limiting access to blood vessels. This overview of skin anatomy shows that, to successfully deliver antibodies to the bloodstream via the transdermal route, it is necessary to manipulate the biophysical properties of the skin, which is permitted by the special cream made in accordance with embodiments herein. The first step in the process will involve some exfoliation to thin up the stratum corneum. If not sufficient, it may be necessary to puncture the stratum corneum wit mechanical devices such as microneedle arrays, which are already used in patients for the delivery of non-protein therapeutics. Once the antibody reaches the epidermis, it will need to reach the blood vessels and enter these vessels. To do this, the cream will include a vasodilator that will transiently open up the underlying blood vessels to let physiological liquids extravasate and enter the deep skin tissues. The local accumulation of liquid mimics a local inflammatory event. Biophysically, it will increase the space between the cells in the epidermis. Plus, the antibody will be able to diffuse more easily in a microenvironment with more biofluids, allowing this antibody to reach and enter dilated blood vessels. Therefore, because the system uses active physiological mechanisms with delivery of a therapeutic agent into the bloodstream, the process must be done in living animals, but can’t be tested in skin biopsies and other in vitro and in silico models of the skin (Schmook et al., 2001; Summerfield et al., 2015; Abd et al., 2016). Blood is collected 24h after cream application, and the plasma separated. Plasma samples to an external contractor to detect the antibody. Study Procedures For this Example, we will use a maximum of 10 male Wistar rats from the Jackson Laboratories split into two batches of 5 animals. The rats will be allowed to get acquainted to the vivarium for two weeks before any procedure is performed. We will use standard animal care procedures for these rats, i.e. water and food ad libitum, 12h dark/light cycles, and daily observations to monitor event pain and distress. Rats will be housed individually to prevent licking of the cream across animals, thus prevent cross-activation of immune responses between rats as much as possible. Plus, a male rat could display aggressive behaviors when housed with other male rats, resulting in injuries. Our single housing procedure will proactively manage this possible issue. We have selected Wistar rats to not have too many animals growing beyond 400- 450 gr. The bigger rats are, the more difficult they are to handle. Thus, we will acquire Wistar rats in the weight range of 150-200 grams, i.e. they will be of young age (4-8 weeks). For the present protocol, we will carry out experiments only on rats that are >250 grams. During the first two weeks of acclimation in the vivarium, the rats will continue to grow and likely reach 250+ grams at the age of 6-10 weeks, per growth chart provided by Charles River Labs. For the experiments, the rats will be anesthetized to prevent the stress associated with restraint and cream application operations. One week prior to each cream application, all rats will be anesthetized for 10-15 min, and 1-1.5 mL of blood will be collected from the tail vein into EDTA tubes. These blood samples are to be used for reference/control during antibody detection experiments. For cream applications, the anesthesia will last 40- 45 minutes. For practical issues, we will handle 1-2 rats per day, thus spread the cream application procedure over 3-4 days. While under anesthesia, one hip of each rat will be shaved, and 250-750 uL of the cream provided by cell medics containing the antibody will be applied with a sterile spatula over a maximum area of 2 x 2 cm (1.5-4 cm2). The duration of anesthesia is chosen to allow most of the cream to penetrate the stratum corneum and epidermis, which should take approximately 30-60 min. This will prevent the rats from removing too much of the cream when licking their hips upon waking up. Also, we have chosen the hips area to apply the cream to prevent rats from scratching behaviors in case of irritation. For information, the cream used in the example has soothing properties and will not develop irritations by itself, but rather prevent irritations. Then the rats will be replaced in their cage. After 22-26h (i.e. on day 2), the rats will be anesthetized again for 10-15 min, and 1-1.5 mL of blood will be collected from the tail vein into EDTA tubes. Because we would like to minimize the pain afflicted to the rats, we want to avoid retro- orbital blood collections. Thus, we selected tail vein blood collections for our present protocol. We are planning that each batch of 5 rats will receive a maximum of 5 cream applications at a frequency of once every 4 weeks. We will alternate rat batches over a 2 week period (i.e. batch #1 will start at week 2, then week 6, 10, etc.; batch #2 will start at week 4, then week 8, 12, etc.). We will also alternate the hip used for the cream application. The first application will be done on the right hip. The second application will be on the left hip, and so on. As explained above, the delivery of antibodies through the skin will likely require exfoliation and vasodilation procedures. The chemicals used to carry out these steps will be integrated into the vehicle cream itself. Repeated cream applications to the same animals for up to 5 applications with a gap of 4 weeks between each application can be performed. As indicated in Table 2, each cream application will be done using a different batch of cream and we will attempt to detect the antibody in the blood before testing a different batch. If the antibody is detected in a batch of animals before the 5th cream application, then the experiment/protocol will stop at the second positive presence of antibody in the plasma. This could happen, after 1, 2, or more formulations of cream have been tested. To note, it is possible that the antibody is not detectable in the blood after 10 different formulations of cream have been tests. Furthermore, if the cream alone is not sufficient for the successful delivery of the antibody after the 6th attempt, we will use a microneedle array to facilitate the puncture of the stratum corneum. After the 5th application to an individual rat, the animal will be euthanized and their carcasses disposed of per federal, state, and local regulations. For the non-immunoreactive and non-toxic antibody, we can share the exact product with other IACUC members, but, if possible, we would like the experimenter (Mr. Kirsh, member of the IACUC) to be blind to the antibody product used for our tests to limit experimental bias. The commercial antibody will be made in mice (close species) and bear a tag that allows for its easy detection in biological samples. Such antibody is frequently used for immunostaining and ELISA procedures, thus is high quality research grade. The antibody will be mixed with the cream before delivery to the rats. The cream is pharmaceutical grade and, as indicated above, has soothing properties. Based on current medical practice with antibodies to treat human diseases, it is possible that rats develop a very mild immune reaction with the production of endogenous antibodies against our test antibody after several applications. However, this reaction is normal and will not endanger the life of the rats. Also unlikely is the possible development of adverse reactions to the antibody, including pain, redness at the site of cream delivery, swelling, and rash. Even less likely is the appearance of symptoms for severe adverse reactions, such as trouble breathing, a severe allergic reaction, fever, changes in blood pressure, and swelling of the face and paws. This is the reason why we are planning daily observations of the animals, as indicated above. Such monitoring will allow us to identify distressed animals and take the appropriate corrective actions to minimize pain and distress. The use of such non- immunological antibody is common in pre-clinical therapeutic research. For example, in a previously published paper, the authors have demonstrated that the main source of allergic reactions for mouse antibodies injected to rats are the Fc fragment of therapeutic antibodies (Tawara et al., 2008). However, the non-immunogenic control IgG1 antibody did not induce any adverse reaction in rats. If necessary, we will be using microneedle arrays to facilitate the penetration of the antibody at the surface of the skin. We will likely use a product by Micropoint (https://micropointtech. com/products/micropoint-patch/). However, we are planning to

of 2 x 2 cm, which will fit the anatomy of rats. Each device will include a matrix of 15 x 15 rows or microneedles. Each microneedle will be 75 μm in length, since the thickness of the stratum corneum in rats is in the range of 4-10 μm (Wei et al., 2017). Microneedle arrays have been used in many experiments with rats. For example, the following publication and figure show how such device was used in the context of orofacial pain: (Ballassini Abdalla H. et al. (2019) Microneedles to Treat Orofacial Pain. Journal of Pharmacology and Experimental Therapeutics: 370 (3) 834-842). Of course, our protocol will apply the cream on the hips, not around the head. Furthermore, we have selected a length of 75 μm for our microneedle arrays because the epidermis thickness reported in normal Wistar rats is ~35 μm (De Bem et al., 2010). While most microneedle arrays used in rats in the literature are generally longer, the goal of such experiments is to directly deliver pre-coated therapeutic agents for passive diffusion directly into the epidermis. On the other hand, our goal when using microneedle arrays is simply to allow the antibody to go under the stratum corneum, not much deeper, as the chemical properties of the cream stimulate active biological mechanisms that will assist with the penetration of the antibody into deeper skin tissues. In addition, it is anticipated that only the distal part of the microneedles (~25-50 μm) will penetrate the stratum corneum, not the full 75 μm. This is congruent with the thickness of the normal epidermis of Wistar rats (De Bem et al., 2010). Thus, our microneedle arrays are adapted to the animal species used in the present protocol and to the biochemical mechanisms activated by the inventive cream. A summary of the study procedure is presented below. Cream applications will take place for sure at weeks 3 and 5. All applications between weeks 9-32 will use improved cream formulations and are optional, i.e. if the antibody is detected in the blood after weeks 3 and 5, we will not continue the protocol. However, if the antibody is not detected at week 5, then we will continue cream applications with improved formulations. If the antibody is still not detected at week 20, then we will attempt to improve drug delivery by using microneedle arrays between weeks 23-32. If no antibody is detected after application #10 (week 32), the current protocol will expire and we will submit a new protocol to the Roseman’s IACUC. Project Summary. All procedures are performed under anesthesia. Cream applications are spread over 3-4 days during the indicated week. WK: week. WK00: Receive 10 male Wistar rats from the Jackson Laboratories 1. Rat Batch #1 (N=5) - WK02: Collect 1-1.5 mL of tail vein blood for control + Isolate plasma by centrifugation - WK03: Shave the right hips + Cream application #1 + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK06: Collect 1-1.5 mL of tail vein blood for control - WK07: Shave the left hips + Cream application #3 (if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK10: Collect 1-1.5 mL of tail vein blood for control - WK11: Shave the right hips + Cream application #5 (if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK14: Collect 1-1.5 mL of tail vein blood for control - WK15: Shave the left hips + Cream application #7 (with microarray if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK18: Collect 1-1.5 mL of tail vein blood for control - WK19: Shave the right hips + Cream application #9 (with microarray if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation + Euthanasia 2. Rat Batch #2 (N=5) - WK04: Collect 1-1.5 mL of tail vein blood for control - WK05: Shave the right hips + Cream application #2 + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK08: Collect 1-1.5 mL of tail vein blood for control - WK09: Shave the left hips + Cream application #4 (if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK12: Collect 1-1.5 mL of tail vein blood for control - WK13: Shave the right hips + Cream application #6 (if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK16: Collect 1-1.5 mL of tail vein blood for control - WK17: Shave the left hips + Cream application #8 (with microarray if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation - WK20: Collect 1-1.5 mL of tail vein blood for control - WK21: Shave the right hips + Cream application #10 (with microarray if required) + Collect 1-1.5 mL of blood after 22-26h + Isolate plasma by centrifugation + Euthanasia The mouse antibody used in the present protocol will be non-immunological and bear a specific tag (such as a biotinylated antibody). Such antibody is not available with a pharmacological grade, but only as research grade. However, the transdermal cream is pharmaceutical grade. Given the antibody quantity will be limited, overall the cream batches applied on the skin of the rats will be very close to pharmaceutical grade. Either the antibody is detected in the blood of the rats, or we reach up to 5 delivery attempts without success, whichever is achieved first. If a rat shows any signs of distress it will also be euthanized. This includes the possible development of pain and/or distress at the site of cream delivery, such as pain, redness, swelling, and rash, or due to adverse reactions to the antibody such as trouble breathing, an allergic reaction, uncontrollable fever, uncontrollable changes in blood pressure, and large swelling of the face and paws. Additional endpoints include >20% weight loss, hunched posture, lethargy with impaired righting reflex or labored breathing, ulcerated skin >2.0 cm. Literature cited Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, Grice JE, Roberts MS (2016) Skin models for the testing of transdermal drugs. Clin Pharmacol 8:163-176. Schmook FP, Meingassner JG, Billich A (2001) Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int J Pharm 215:51-56. Summerfield A, Meurens F, Ricklin ME (2015) The immunology of the porcine skin and its value as a model for human skin. Mol Immunol 66:14-21. Abd E, Yousef SA, Pastore MN, Telaprolu K, Mohammed YH, Namjoshi S, Grice JE, Roberts MS (2016) Skin models for the testing of transdermal drugs. Clin Pharmacol 8:163-176. Example 2. Transdermal Formulation of Biotinylated Mouse Fab Antibody. Biotinylated mouse Fab Antibody formulated in a topical cream is provided in Table 3 and was applied to the skin of rats, generally according to Example 1. The biotin concentration was measured in plasma following application to the rat’s skin. Results are shown in FIGS. 5 and 6. Table 3. Formulation of Fab Antibody. Glycerin % Glycerin Gl rin m g g E g

Mouse IgG, Fab fragment, Jackson Immuno 0.20% 5.00 Research # 015-060-007 (lyophilized 1 mg

. . Semaglitude (Ozempic) Target systemic/bloodstream Topical cream applied to the skin (amounts by weight) Glycerin 20-40% Caprylic Capric Triglycerides (CCT) 5-15% Salicylic Acid (SA) 2-5% Ceatearyl Alcohol and polysorbate 60 2-15% Beeswax 1-6% Cell Penetrating Peptide (CPP) 0.1%-1% Oleic Acid (OA) 10-30% Azone 1-5% Diethylene Glycol Monoethyl Ether (DEGEE) 5-30% Semaglitude 0.1-6% Example 4. mRNA Vaccine Pharmaceutical Composition. Target systemic Topical formulation applied to skin (amounts by weight) Isopropyl Mysistate (IPM) 5-20% Glycerin 20-40% Caprylic Capric Triglycerides (CCT) 5-15% Salicylic Acid (SA) 2-6% Ceatearyl Alcohol and polysorbate 60 5-10% DMSO 1-10% Cell Penetrating Peptide (CPP) 0.1-6% Oleic Acid (OA) 5-30% Terpenes 1-6% Diethylene Glycol Monoethyl Ether (DEGEE) 5-30% mRNA 0.1-5% Example 5. Chemotherapeutics Pharmaceutical Composition. Target breast tumor Topical cream applied to skin (amounts by weight) CHEMOTHERAPEUTICS 1-10% CELL PENETRATING PEPTIDE 0.25-2% GLYCERIN 5-40% L-ASCORBIC ACID 2-30% CAPRIC/CAPRYLIC TRIGYLCERIDE 5-25% ISOPROPYL MYRISTATE 5-30% DIETHYLENE GLYCOL MONOETHYL E_THER ^5-30% CEATEARYL ALCOHOL (and) P_{OLYSORBATE 60} ^2-15% BEESWAX (white)

BENTONE GEL GTCC V SALICYCLIC ACID 1-3% BHT 0.25-2% PARABENS 0.50% TRIHYDROXYSTEARIN (THIXCIN R) 0.50% Example 6. Antibody Pharmaceutical Composition. Target systemic/bloodstream Topical formulation applied to skin (amounts by weight) Glycerin 5-30% Isopropyl Mysistate (IPM) 5-20% Salicylic Acid (SA) 2-5% Cell Penetrating Peptide (CPP) 0.1%-1% Oleic Acid (OA) 2-20% Diethylene Glycol Monoethyl Ether (DEGEE) 2-30% DMSO 1-10% mAbs 0.1-3% Example 7. Oligonucleotide Pharmaceutical Composition. Target eye tissues Topically applied liquid to the eye (amounts by weight) Glycerin 5-30% Isopropyl Mysistate (IPM) 5-20% Salicylic Acid (SA) 2-5% Cell Penetrating Peptide (CPP) 0.1%-1% Oleic Acid (OA) 2-20% Diethylene Glycol Monoethyl Ether (DEGEE) 2-30% siRNA 0.1-2% While the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art. Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.

Claims

WHAT IS CLAIMED IS: 1. A pharmaceutical composition for topical application for delivery of a bioactive agent to a subject, wherein the composition comprises i) an anhydrous carrier; ii) an effective amount of a bioactive agent; and iii) a penetration enhancer selected from the group consisting of an amino acid derivative compound, a cell penetrating peptide (CPP), an antimicrobial peptide, a lipid nanoparticle composition, and combinations thereof.

2. The pharmaceutical composition of claim 1, wherein the anhydrous carrier comprises one or more esters, amides, ethoxylated fats, mineral oil, petrolatum, vegetable oils, animal fats, triglycerides, polyols (e.g., glycerol), glycerin, propylene glycol, sorbitol, isopropyl myristate and combinations thereof.

3. The pharmaceutical composition of any of claims 1 or 2, wherein the anhydrous carrier comprises glycerin in a concentration of 5-40% by weight.

4. The pharmaceutical composition of any of claims 1-3, wherein the anhydrous carrier comprises capric/caprylic triglyceride, glycerol, beta hydroxy acid, and one or more of azone, urea, pyrrolidones, essential oils, terpenes and terpenoids, oxazolidinones, propylene glycol, epidermal enzymes, oleic acid, dimethyl isosorbide, sulphoxides, dimethylsulfoxide, dimethylsulfone, ethanol, diethylene glycol monoethyl ether, hyalauronic acid, chitin, mucopolysaccharides, fatty acids, linoleic acid, alpha linoleic acid, cod liver oil, menthol, menthol derivatives, squalene, glycerol derivatives, and glycerol monoethers.

5. The pharmaceutical composition of any of claims 1-4, wherein the composition comprises the amino acid derivative compound, wherein the amino acid derivative compound has the following configuration: (AA) ---- (L) ---- (HP), wherein AA is an amino acid or a group of two amino acid molecules linked together by a peptide bond or an alkylene chain linking group having up to six carbon atoms, wherein L is a linker group, and wherein HP is a hydrophobic moiety.

6. The pharmaceutical composition of claim 4, wherein HP is an alkyl or alkenyl hydrocarbon chain having a length of from 10 to 20 carbon atoms.

7. The pharmaceutical composition of any of claims 4-6, wherein L is selected from the group consisting of a single bond, a carbonyl group, -C(O)-O-CH2, -C(O)-O- CH₂CH₂-, -C(O)-NH-CH₂- and –C(O)-NH-CH₂CH₂-.

8. The pharmaceutical composition of any of claims 4-7, wherein the amino acid(s) are selected from the group consisting of arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, 6-(dimethylamino)hexanoic acid, derivatives thereof, and combinations thereof.

9. The pharmaceutical composition of any of claims 1-8, wherein the amino acid derivative is selected from a compound identified in Table 1, or a combination thereof.

10. The pharmaceutical composition of any of claims 1-9, wherein the composition comprises a cell penetrating peptide.

11. The pharmaceutical composition of claim 10, wherein the peptide consists of six to twenty amino acid residues.

12. The pharmaceutical composition of claim 10 or 11, wherein at least 50% of the amino acid residues of each peptide are positively charged at physiological pH.

13. The pharmaceutical composition of claim 12, wherein the positively charged amino acid residues are selected from arginine and lysine.

14. The pharmaceutical composition of any of claims 1-4, wherein the penetration enhancer is an antimicrobial peptide.

15. The pharmaceutical composition of claim 14, wherein the antimicrobial peptide is a magainin peptide.

16. The pharmaceutical composition of claim 10, wherein the cell penetrating peptide is selected from the group consisting of any of SEQ ID NOS:1-47 and combinations thereof.

17. The pharmaceutical composition of any of claims 1-16, wherein the composition comprises a lipid nanoparticle composition.

18. The pharmaceutical composition of claim 17, wherein the lipid nanoparticle composition comprises one or more cationic lipids.

19. The pharmaceutical composition of any of claims 1-18, wherein the bioactive agent is selected from a biologic, protein, vaccine, macromolecule, and a small molecule.

20. The pharmaceutical composition of claim 19, wherein the bioactive agent is an antibody.

21. A method of treating a disease or condition in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of any of claims 1- 20.

22. The method of claim 21, wherein the composition is administered topically to the subject for local site-specific or systemic drug delivery including cutaneous, transdermal, ocular, intra-articular, musculoskeletal, intra-tympanic (local ear), transungual drug delivery or combinations thereof.

23. The method of claim 21 or 22, wherein effective amounts of the bioactive agent are absorbed into the subject’s blood circulation to treat the disease or condition.

24. The method of any of claims 21-23, wherein the method further comprises exfoliating skin of the subject prior to the administering step.

25. The method of any of claims 21-24, wherein the pharmaceutical composition is administered with or in combination with a microneedle array.

26. The method of claim 25, wherein the subject is treated with a microneedle array to disrupt the stratum corneum prior to administration of the pharmaceutical composition.

27. The method of claim 26, wherein the pharmaceutical composition is injected into the skin with a microneedle array.