WO2023116517A1 - 一种可平稳释放的持续性递送制剂及其制备方法 - Google Patents

一种可平稳释放的持续性递送制剂及其制备方法 Download PDF

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WO2023116517A1
WO2023116517A1 PCT/CN2022/138871 CN2022138871W WO2023116517A1 WO 2023116517 A1 WO2023116517 A1 WO 2023116517A1 CN 2022138871 W CN2022138871 W CN 2022138871W WO 2023116517 A1 WO2023116517 A1 WO 2023116517A1
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Prior art keywords
preparation
gel
delivery formulation
active pharmaceutical
biodegradable polymer
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PCT/CN2022/138871
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English (en)
French (fr)
Inventor
苏正兴
杨依凡
赵金龙
徐伟
杨雪媛
赵栋
刘思川
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Hunan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Original Assignee
Hunan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Co Ltd
Sichuan Kelun Pharmaceutical Research Institute Co Ltd
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Application filed by Hunan Kelun Pharmaceutical Research Co Ltd, Sichuan Kelun Pharmaceutical Research Co Ltd, Sichuan Kelun Pharmaceutical Research Institute Co Ltd filed Critical Hunan Kelun Pharmaceutical Research Co Ltd
Priority to US18/704,109 priority Critical patent/US20240415765A1/en
Priority to CN202280071537.XA priority patent/CN118201599A/zh
Priority to JP2024525786A priority patent/JP2024546571A/ja
Priority to EP22909831.4A priority patent/EP4454636A4/en
Publication of WO2023116517A1 publication Critical patent/WO2023116517A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the disclosure belongs to the technical field of pharmaceutical preparations, and in particular relates to a sustained delivery preparation capable of steady release and a preparation method for the delivery preparation.
  • ISFI is a new drug delivery system composed of biodegradable polymer solution or semi-solid, which can be solidified/gelled at the injection site to form a reservoir .
  • ISFI is mainly formed through different mechanisms such as in situ precipitation, organogelation, or polymer crosslinking.
  • solvent diffusion induced in situ precipitation system is currently the most marketed and widely used technology, and many commercial products have been launched, and it is effective in the treatment of periodontitis advanced pancreatic cancer Opioid Use Disorder and schizophrenia Widely used in other fields.
  • in situ gel has the advantages of simple preparation process, convenient injection, and easy production and scale-up.
  • the release of drugs in the in situ gel in vivo can be mainly divided into three stages: the burst release stage, the diffusion stage and the polymer degradation stage (as shown in Figure 2).
  • the burst release stage mainly refers to the phase separation of the organic solvent and the interstitial fluid when the preparation is injected, resulting in the rapid release of the drug.
  • a large number of studies have shown that the drug release at this stage can reach between 8% and 95%.
  • the drugs used for treatment usually have a narrow safety window, and the fluctuation range of blood drug concentration needs to be strictly controlled. rapid increase, leading to serious side effects.
  • the in-situ gel preparation drug has a large release amount in the burst release stage in the body.
  • the present disclosure provides a sustained delivery preparation that can be released smoothly, which solves the problem of large initial burst release of traditional in-situ gel (Atrigel technology) problem.
  • a delivery formulation comprising an active pharmaceutical ingredient and a gel carrier, wherein the gel carrier comprises a biodegradable polymer, an organic solvent, and a hydrophobic additive and optionally a hydrophilic gel skeleton material.
  • hydrophobic additive is selected from the group consisting of ethyl acetate, medium chain triglycerides, glyceryl triacetate, glyceryl tricaprylate, benzyl benzoate and benzene
  • the hydrophobic additive is selected from one or more of benzyl benzoate, glyceryl triacetate and glyceryl tricaprylate.
  • hydrophilic gel matrix material is selected from poloxamer, carbomer, polyvinylpyrrolidone, hydroxyl One or more of propyl methylcellulose and sodium carboxymethylcellulose; preferably, the hydrophilic gel matrix material is selected from one of poloxamer 188, carbomer and polyvinylpyrrolidone one or more species.
  • the biodegradable polymer is selected from polyester or polyester copolymer; preferably, the biodegradable The degradable polymer is selected from polylactide or lactide/glycolide copolymer; preferably, the biodegradable polymer is selected from lactide/glycolide copolymer; more preferably, the lactide
  • the molar ratio of lactide to glycolide in the /glycolide copolymer is 50:50-95:5; and/or the molecular weight of the biodegradable polymer is 5000-70000Da; and/or the biodegradable
  • the polymer accounts for 20%-50% of the total mass of the gel carrier.
  • the present disclosure provides a sustained-delivery formulation that can be released smoothly. Compared with the in-situ gel prepared by traditional Atrigel technology, after adding a small amount of hydrophobic additive and optional hydrophilic gel matrix material, it has a significant slowdown of drug body. The effect of internal and external burst release, and the blood drug concentration in the body can be maintained within a safe and effective range for more than one week. At the same time, the preparation method of the preparation is simple and suitable for large-scale production. Also, the finished delivery formulation is convenient to use.
  • Figure 1 is Schematic diagram of the composition of the product.
  • Figure 2 is Schematic diagram of the release mechanism of the product.
  • Figure 3 is a schematic diagram of the composition of the delivery formulation of the present disclosure.
  • Fig. 4 is the drug concentration vs time curves of the samples in Examples 5, 10, 11, and 12 within 504 h in rats.
  • Fig. 5 is the drug concentration vs time curves of samples in Examples 13, 14, and 15 within 240 h in rats.
  • Fig. 6 is the drug concentration vs time curve of the sample in the rat body in 312h in Example 28.
  • Fig. 7 is the drug concentration vs time curves of samples in Examples 1, 3, and 5 within 504 h in rats.
  • Fig. 8 is the drug concentration vs time curves of samples in Examples 10, 11, and 12 within 504 hours in rats.
  • Fig. 9 is the drug concentration vs time curves of samples in Examples 13 and 14 within 720 h in rats.
  • Fig. 10 is the drug concentration vs time curves of samples in Examples 15, 16, 29, and 30 within 720 h in rats.
  • a numerical range represented by “numerical value A - numerical value B" or “numerical value A-numerical value B” refers to a range including numerical values A and B at the endpoints.
  • the meaning expressed by “may” includes both meanings of performing certain processing and not performing certain processing.
  • “optional” or “optionally” means that the next described event or situation may or may not occur, and that the description includes situations where the event occurs and situations where the event does not occur.
  • one (a)” or “one (an)” or “one (the)” may mean “one”, and may also mean “one or more”, “at least one” and “one or more than one”.
  • the term "about” may mean that a value includes the standard deviation of error of the apparatus or method used to determine the value.
  • the numerical ranges and parameters used to define the present disclosure are approximate numerical values, and the relevant numerical values in the specific examples have been presented here as precisely as possible. Any numerical value, however, inherently contains standard deviations resulting from the foregoing testing apparatus or methodology. Therefore, unless expressly stated otherwise, it should be understood that all ranges, numbers, values and percentages used in this disclosure are modified by “about”. As used herein, “about” generally means that the actual value is within ⁇ 10%, ⁇ 5%, ⁇ 1%, or ⁇ 0.5% of a particular value or range.
  • PLGA 7525 DLG 2A
  • “7525” means that the molar ratio of lactide to glycolide is 75:25
  • “DLG” means lactide /glycolide copolymer, if "DL” means polylactide
  • “2" is the intrinsic viscosity mark, where 1 means that the intrinsic viscosity is 0.05-0.15dL/g, 1.5 means that the intrinsic viscosity is 0.10-0.20dL/g, 2 means the intrinsic viscosity is 0.15-0.25dL/g, 2.5 means the intrinsic viscosity is 0.20-0.30dL/g, 3 means the intrinsic viscosity is 0.25-0.35dL/g, 3.5 means the intrinsic viscosity is 0.30-0.40dL/g, 4 means The intrinsic viscosity is 0.35-0.45dL/g, 4.5 means the intrinsic viscosity is 0.40-0.50dL/g,
  • the present disclosure provides, in a first aspect, a gel carrier comprising a biodegradable polymer, an organic solvent, and a hydrophobic additive and optionally a hydrophilic gel framework material.
  • gel carrier refers to a substance or a composition of substances for encapsulating, delivering and/or releasing bioactive agents or active pharmaceutical ingredients, such as comprising biodegradable polymers and organic solvents .
  • the gel carrier of the present disclosure comprises a biodegradable polymer, an organic solvent, and a hydrophobic additive and optionally a hydrophilic gel matrix material. In some more specific embodiments, the gel carrier of the present disclosure comprises a biodegradable polymer, an organic solvent, and a hydrophobic additive. In other more specific embodiments, the gel carrier of the present disclosure comprises a biodegradable polymer, an organic solvent, a hydrophobic additive and a hydrophilic gel matrix material.
  • biodegradable polymers are used interchangeably to refer to polymers that can be decomposed by chemical or physical means when interacting with the physiological environment.
  • the polymer eg, at the implant site in the subject, erodes, decomposes or dissolves over a period of time, eg, days, weeks or months.
  • Biodegradable polymers serve a temporary purpose in a subject, such as delivering a bioactive agent such as a drug.
  • Biodegradable polymers can degrade into pieces and be metabolized or excreted by the host.
  • the present disclosure does not specifically limit the specific types of biodegradable polymers, which can be determined by those skilled in the art according to actual needs.
  • a biodegradable polymer may be a polyester, which refers to a polymer in which all or substantially all repeat units are linked together by ester groups.
  • Polyesters can be formed by reacting monomers having carboxyl and hydroxyl groups to form ester groups.
  • Polyesters can be formed by ring-opening polymerization of cyclic ester monomers.
  • Polyesters can be formed from monomers such as glycolide, lactide, ⁇ -caprolactone or p-dioxanone.
  • the biodegradable polymers of the present disclosure are selected from polylactides.
  • the biodegradable polymer may be absorbable polyester copolymers, terpolymers, tetrapolymers or mixtures thereof.
  • Suitable absorbable polyester copolymers include, but are not limited to, lactide/glycolide copolymer, ⁇ -caprolactone/glycolide copolymer, lactide/trimethylene carbonate copolymer, lactide/ Glycolide/Caprolactone Terpolymer, Lactide/Glycolide/Trimethylene Carbonate Terpolymer, Lactide/Caprolactone/Trimethylene Carbonate Terpolymer, Glycolide ester/caprolactone/trimethylene carbonate terpolymer, and lactide/glycolide/caprolactone/trimethylene carbonate tetrapolymer.
  • the biodegradable polymers of the present disclosure are selected from lactide/glycolide copolymers (polylactic-co-glycolic acid).
  • the molar ratio of lactide to glycolide in the lactide/glycolide copolymer used in the present disclosure is 50:50-95:5; 50:50, 75:25, 85:15 or 95:5 etc.
  • the disclosure does not specifically limit the molecular weight of the biodegradable polymer, which can be determined by those skilled in the art according to actual needs.
  • the molecular weight of the biodegradable polymer of the present disclosure is 5000-70000Da, preferably 10000-50000Da; exemplary, it can be 5000Da, 10000Da, 15000Da, 20000Da, 25000Da, 30000Da, 35000Da, 40,000Da, 45,000Da, 50,000Da, 55,000Da, 60,000Da, 65,000Da, 70,000Da, or any numerical value within the stated range, etc.
  • the content of the biodegradable polymer can be adjusted within a certain range according to specific needs.
  • the content of the biodegradable polymer of the present disclosure accounts for 20%-50% of the total mass of the gel carrier in terms of mass percentage; exemplary, it can be 20%, 23%, 25% , 27%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45 %, 46%, 47%, 48%, 49% or 50%, etc.
  • the content of the biodegradable polymer of the present disclosure accounts for 30%-50% of the total mass of the gel carrier in terms of mass percentage.
  • a biodegradable polymer may also be a polyetherester, which refers to a polymer in which all or substantially all repeating units are linked together by ester groups or ether groups, and in which both ether groups and ester groups serve as linkages. groups present in the polymer.
  • the biodegradable polymer may be a polyether/polyester polymer, which is a polyetherester having a block copolymer structure comprising one or more repeating units linked together by ether groups Blocks and blocks of one or more repeating units linked together by ester groups.
  • organic solvent refers to a biocompatible organic solvent that can diffuse in a living body, be metabolized or absorbed by a living body.
  • organic solvent for example, N-methylpyrrolidone, ethyl acetate, medium-chain triglycerides, triacetin, tricaprylin, benzyl benzoate, benzyl alcohol, dimethyl sulfoxide, ethyl benzoate, Ethanol, glycerol furfural and glycerol formal, etc.
  • the organic solvent of the present disclosure is N-methylpyrrolidone and/or dimethyl sulfoxide. In some specific embodiments, the organic solvent of the present disclosure is N-methylpyrrolidone. In other specific embodiments, the organic solvent of the present disclosure is dimethyl sulfoxide. In some specific embodiments, the organic solvents of the present disclosure are N-methylpyrrolidone and dimethyl sulfoxide.
  • the content of the organic solvent can be adjusted within a certain range according to specific needs.
  • the mass ratio of the organic solvent of the present disclosure to the hydrophobic additive is 1:1-9:1; exemplary, it can be 1:1, 2:1, 3:1, 4:1 , 5:1, 6:1, 7:1, 7:3, 8:1 or 9:1 etc.
  • the content of the organic solvent of the present disclosure accounts for 20%-60% of the total mass of the gel carrier in terms of mass percentage; exemplarily, it can be 20%, 25%, 30%, 35% , 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55 %, 56%, 57%, 58%, 59% or 60%, etc.
  • hydrophobic additive may be a pharmaceutically acceptable additive having hydrophobicity, and does not include hydrophobic active substances or active ingredients.
  • hydrophobic active substances or active ingredients for example, fatty alcohols such as stearyl alcohol, fatty acids such as sorbic acid, fatty acid esters such as medium chain triglycerides, silicone compounds such as dimethylsiloxane, etc. in the art.
  • the hydrophobic additive of the present disclosure is selected from one or more of ethyl acetate, medium chain triglycerides, glyceryl triacetate, glyceryl tricaprylate, benzyl benzoate and benzyl alcohol. In some specific embodiments, the hydrophobic additive of the present disclosure is selected from one or more of triacetin, tricaprylin and benzyl benzoate.
  • the content of the hydrophobic additive can be adjusted within a certain range according to specific needs.
  • the content of the hydrophobic additive of the present disclosure accounts for 1%-50% of the total mass of the gel carrier in terms of mass percentage; exemplarily, it can be 1%, 5%, 6%, 7% , 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24 %, 25%, 30%, 35%, 40%, 45% or 50%, etc.
  • the content of the hydrophobic additive of the present disclosure accounts for 5%-30% of the total mass of the gel carrier in terms of mass percentage.
  • hydrophilic gel skeleton material is a kind of auxiliary material used as a carrier material, mainly to adjust the drug release rate, to play the role of slow release and controlled release, so that the drug release rate and release amount in the preparation can meet the appropriate requirements , to ensure that the drug is delivered to the patient site at a certain rate, and maintain a certain concentration in the body, so as to obtain the expected effect and reduce side effects.
  • the gel carrier of the present disclosure comprises a hydrophilic gel matrix material. In other specific embodiments, the gel carrier of the present disclosure does not contain a hydrophilic gel matrix material.
  • the hydrophilic gel matrix material can be a hydrophilic polymer, such as natural gum, such as alginate, agar, xanthan gum, tragacanth, etc.; cellulose derivatives, such as methyl cellulose (MC), sodium carboxymethylcellulose (CMC-Na), hypromellose (HPMC), hydroxyethylcellulose (HEC), etc.; non-cellulose polysaccharides, such as chitin, chitosan, Carbomer, etc.; polymers, such as povidone (PVP), ethylene polymers, acrylic resins, polyvinyl alcohol (PVA), etc.
  • natural gum such as alginate, agar, xanthan gum, tragacanth, etc.
  • cellulose derivatives such as methyl cellulose (MC), sodium carboxymethylcellulose (CMC-Na), hypromellose (HPMC), hydroxyethylcellulose (HEC), etc.
  • non-cellulose polysaccharides such as chitin, chi
  • the hydrophilic gel skeleton material of the present disclosure is selected from one of poloxamer, carbomer, polyvinylpyrrolidone, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or more. In some more specific embodiments, the hydrophilic gel matrix material of the present disclosure is selected from one or more of poloxamer 188, carbomer and polyvinylpyrrolidone.
  • the content of the hydrophilic gel skeleton material can be adjusted within a certain range according to specific needs.
  • the content of the hydrophilic gel skeleton material of the present disclosure accounts for 0.5%-15% of the total mass of the gel carrier in terms of mass percentage; exemplary, it can be 0.5%, 1%, 2% %, 3%, 4%, 5%, 7%, 10%, 12% or 15%, etc.
  • the content of the hydrophilic gel framework material of the present disclosure accounts for 1%-5% of the total mass of the gel carrier in terms of mass percentage.
  • the present disclosure provides a delivery formulation comprising an active pharmaceutical ingredient and the gel carrier provided in the above ⁇ first aspect> of the present disclosure.
  • a "delivery formulation” is a pharmaceutical composition containing an active pharmaceutical ingredient (API) and a gel carrier (in some cases, only the active pharmaceutical ingredient and a gel carrier), which is administered to The subject can then release the active pharmaceutical ingredient with a specific release profile (eg, smooth, slow and sustained).
  • API active pharmaceutical ingredient
  • gel carrier in some cases, only the active pharmaceutical ingredient and a gel carrier
  • the delivery formulations of the present disclosure comprise an active pharmaceutical ingredient and a gel carrier, wherein the gel carrier comprises a biodegradable polymer, an organic solvent, and a hydrophobic additive and optionally a hydrophilic gel matrix material.
  • the delivery formulations of the present disclosure comprise an active pharmaceutical ingredient, a biodegradable polymer, an organic solvent, and a hydrophobic additive.
  • the delivery formulations of the present disclosure comprise an active pharmaceutical ingredient, a biodegradable polymer, an organic solvent, a hydrophobic additive, and a hydrophilic gel matrix material.
  • active pharmaceutical ingredient refers to any substance or mixture of substances in a delivery formulation that is pharmacologically active or otherwise useful in the diagnosis, treatment, alleviation, management, or prevention of a disease Act directly or be able to affect the function or structure of the body.
  • the active pharmaceutical ingredients of the present disclosure may be selected from drugs or hormonal drugs for treating schizophrenia.
  • the active pharmaceutical ingredients of the present disclosure include but are not limited to risperidone, paliperidone, bupivacaine, ropivacaine, leuprolide, triptorelin, octreotide, Gautin, pramipexole, lumepirone or pharmaceutically acceptable salts thereof, etc.
  • the active pharmaceutical ingredient of the present disclosure is selected from rotigotine, pramipexole, lumepirone or pharmaceutically acceptable salts thereof, and the like.
  • the content of active pharmaceutical ingredients can be adjusted within a certain range according to specific needs.
  • the content of the active pharmaceutical ingredient is calculated in its free base form.
  • the content of active pharmaceutical ingredients is calculated in the form of their acid addition salts.
  • the content of the active pharmaceutical ingredient in the delivery formulation of the present disclosure is 0.5%-30% by mass percentage; exemplary, it can be 0.5% %, 1%, 2%, 3%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 6%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8% , 6.9%, 7%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 8%, 8.5%, 9%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or
  • the present disclosure provides a preparation method of the gel carrier provided in the above ⁇ first aspect> of the present disclosure.
  • the preparation method of the gel carrier of the present disclosure may include the following steps: taking a prescription amount of biodegradable polymers, organic solvents, hydrophobic additives and optional hydrophilic gel framework materials, and mixing them to Uniform, that is.
  • the present disclosure provides a preparation method of the delivery formulation provided in the above ⁇ second aspect> of the present disclosure.
  • the preparation method of the delivery formulation of the present disclosure may include the following steps: taking a prescribed amount of biodegradable polymers, organic solvents, hydrophobic additives and optional hydrophilic gel matrix materials, and mixing until uniform , and then add the active pharmaceutical ingredient (for example, the prescription amount of the active pharmaceutical ingredient), mix until uniform, and obtain.
  • the preparation method of the delivery formulation of the present disclosure may include the following steps: taking the prescribed amount of biodegradable polymer, organic solvent, hydrophobic additive and optional hydrophilic gel matrix material, mixing until uniform , before use, add the active pharmaceutical ingredient (for example, the active pharmaceutical ingredient in the prescribed amount), mix until uniform, and obtain.
  • adding the active drug just before use helps to ensure the stability of the delivery formulation.
  • the preparation method of the delivery formulation of the present disclosure may include the following steps: taking a prescribed amount of biodegradable polymers, organic solvents, hydrophobic additives and optional hydrophilic gel matrix materials, and mixing them to Homogeneous, immediately add the active pharmaceutical ingredients (for example, the prescription amount of active pharmaceutical ingredients), mix until homogeneous, and that is ready.
  • active pharmaceutical ingredients for example, the prescription amount of active pharmaceutical ingredients
  • the preparation method of the delivery formulation of the present disclosure may include the following steps: taking a prescription amount of biodegradable polymer, active pharmaceutical ingredient, organic solvent, hydrophobic additive and optional hydrophilic gel matrix Materials, mixed until uniform, that is.
  • the gel carrier components there is no need to dissolve and mix the gel carrier components in advance, and it can be directly mixed with the active pharmaceutical ingredients to a uniform level, so that it is not necessary to consider the dissolution order of the ingredients and the timing of adding the active pharmaceutical ingredients, and it will not affect the
  • the stability of the delivery preparation during storage has a negative impact, which greatly improves the convenience of storage, transportation and use of the delivery reagent.
  • composition of the delivery formulation of the present disclosure is shown in Figure 3.
  • the instruments, reagents, materials, experimental animals, etc. used in the present disclosure can be obtained through conventional commercial means.
  • Hydrophobic additive content 1, 2, 3 Hydrophobic additive content, hydrophilic gel skeleton material, and PLGA content are the weight ratios of each in the gel carrier (excluding API);
  • the drug loading is the mass ratio of API to the total preparation (including API), and the salt forms such as pramipexole pamoate and pramipexole palmitate are all converted in the form of free base.
  • Example 10 40 5050 DLG 2E 25 1851
  • Example 11 30 5050 DLG 4.5A 25 6349
  • Example 12 30 7525 DLG 5.5E 25 7756
  • Example 13 35 5050 DLG 4.5A 25 17865
  • Example 14 35 7525 DLG 5.5E 25 19409
  • Example 15 45 7525 DLG 2A 25 1988
  • Example 29 45 7525 DLG 2A 25 1156
  • the results of Examples 10-15 and 29 show that the viscosity of the formulation is mainly related to the molecular weight and concentration of PLGA, the greater the molecular weight or concentration of PLGA, the greater the viscosity of the formulation; in addition, the hydrophobic additive will also increase the viscosity of the formulation.
  • the greater the viscosity of the preparation the slower the release of the drug in vitro.
  • the main reason may be that the increase in viscosity makes the gel carrier more dense, which increases the resistance of the carrier to the drug, making it difficult for the external medium to enter the gel. Backbone, the degradation of PLGA is slowed down, thus slowing down the release.
  • the gel viscosity and the ratio of lactide:glycolide in the polymer will affect the sustained release effect of the drug.
  • Examples 1-5 compared with Example 1, after adding a certain proportion of hydrophobic additives such as benzyl benzoate, glyceryl triacetate or glyceryl tricaprylate in Examples 2-5, the burst release of the preparation was significantly 1h/24h reduce.
  • Examples 6-9 compared with Example 6, after adding a small amount of hydrophilic gel matrix material in Examples 7-9, the 1h burst release was significantly reduced.
  • Examples 10-12 Screening the influence of different types of PLGA on the release rate of preparations, the 5050 DLG 4.5A group preparations have a small burst release in 24 hours, and the release period is mainly related to the molecular weight of the polymer, which is significantly prolonged with the increase of molecular weight, 5050 DLG
  • the release cycle of 4.5A and 7525 DLG 5.5E groups was significantly longer than that of 5050 2E group, and the release cycle of 7525 DLG 5.5E was the longest.
  • the concentration of PLGA was increased while the drug load was reduced, and different PLGA optimal prescription combinations were further screened. Increase.
  • Hydrophobic additives can significantly reduce burst release, but different types of PLGA have different effects on burst release, and polymer molecular weight and lactide-glycolide ratio will affect the burst release effect.
  • Examples 19-24 compared with Examples 19, 21, and 23, after the corresponding Examples 20, 22, and 24 added a certain proportion of hydrophobic additives and hydrophilic gel matrix materials, the burst release of the drug in 1h/24h was significantly Reduced, and the release period is prolonged, and the blood drug concentration in the body can be maintained within a safe and effective range for more than one week.
  • Examples 25-28 compared with Example 25, after certain hydrophobic additives were added in Examples 26-28, the 1h/24h burst release decreased.
  • the dosage is 10 mg/kg (calculated as rotigotine), subcutaneously inject the preparation in the above-mentioned part of the embodiment, take blood from the tail vein at the predetermined time point, after the plasma sample is processed by SPE (Solid-Phase Extraction), use LC - Determination of rotigotine concentration by MS/MS method.
  • Example 5 10-12 samples in vivo drug concentration curves in rats (within 504h) are shown in Figure 4.
  • the dosage is 5 mg/kg (calculated as rotigotine), subcutaneously inject the preparations in some of the above examples, take blood from the tail vein at the predetermined time point, and after the plasma sample is processed by SPE (Solid-Phase Extraction), use LC - Determination of rotigotine concentration by MS/MS method.
  • the variation curves of the drug concentration of the samples of Examples 13-15 in rats with time (within 240 h) are shown in Fig. 5 .
  • the dosage is 10.5 mg/kg (calculated as lumepirone), subcutaneously inject the preparation in the above-mentioned part of the embodiment, take blood from the tail vein at the predetermined time point, and after the plasma sample is processed by SPE (Solid-Phase Extraction), use
  • the concentration of lumepirone was determined by LC-MS/MS.
  • the variation curve of the drug concentration of the sample of Example 28 in rats with time (within 312 h) is shown in FIG. 6 .
  • the in situ gel prepared by traditional Atrigel technology (active ingredients are rotigotine, pramipexole, lumepirone, etc.) has a large burst release in vitro, and is not suitable for drugs with a narrow safe therapeutic window.
  • Additives such as benzyl benzoate, glyceryl triacetate, glyceryl tricaprylate, medium chain triacetin, etc.
  • optional hydrophilic gel matrix materials such as poloxamer, sodium carboxymethylcellulose, Carbomer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, etc.

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Abstract

一种可平稳释放的持续性递送制剂及其制备方法。该制剂包含活性药物成分和凝胶载体，该凝胶载体包含生物可降解聚合物、有机溶剂、疏水添加剂和任选的亲水凝胶骨架材料。该递送制剂相比传统Atrigel技术制备的原位凝胶，在添加少量疏水添加剂和任选的亲水凝胶骨架材料后，具有减缓药物体内外突释的效果，且体内血药浓度在安全有效范围内可维持超过一周。该制剂制备方法简单。

Description

一种可平稳释放的持续性递送制剂及其制备方法
相关申请的引用
本公开要求于2021年12月24日提交中国专利局、申请号为202111598937.X、发明名称为“一种可平稳释放的持续性递送制剂及其制备方法”的发明专利申请的优先权，通过引用将其全部内容结合在本公开中。
技术领域
本公开属于药物制剂技术领域，具体涉及一种可平稳释放的持续性递送制剂，以及该递送制剂的制备方法。
背景技术
原位形成植入物(In situ forming implant(s),ISFI)是由生物可降解的聚合物溶液或半固体组成的，能在注射部位凝固/凝胶化而形成储库的新型给药系统。根据制剂组成，ISFI主要通过原位沉淀、有机胶凝或聚合物交联等不同机制形成。其中基于溶剂扩散诱导原位沉淀的
Figure PCTCN2022138871-appb-000001
system是目前市场化的、应用最多的技术，已有多个商业产品上市，在治疗牙周炎
Figure PCTCN2022138871-appb-000002
晚期胰腺癌
Figure PCTCN2022138871-appb-000003
阿片类物质使用障碍
Figure PCTCN2022138871-appb-000004
以及精神分裂症
Figure PCTCN2022138871-appb-000005
等领域广泛应用。
Dunn等人最早在1987年提出了
Figure PCTCN2022138871-appb-000006
技术相关概念(如图1所示)。其主要是将生物可降解聚合物载体(丙交酯/乙交酯共聚物(poly(lactic-co-glycolic)，PLGA)，聚丙交酯(polylactic acid，PLA))与有机溶剂(N-甲基吡咯烷酮(N-methyl pyrrolidone，NMP))混溶，形成载体系统，再将小分子、多肽或大分子药物等溶解或分散于其中，形成可注射的溶液或混悬液。制剂注射后，溶剂扩散发生相分离，渗透到周围组织液中，聚合物在注射部分沉淀形成半固体至固体的药物储库，从而达到长效释放的效果。由于制剂特征，
Figure PCTCN2022138871-appb-000007
原位凝胶与传统的固体植入剂和微球相比，具有制备工艺简单，注射方便，易于生产放大等优势。
由于制剂形成原理，
Figure PCTCN2022138871-appb-000008
原位凝胶制剂往往具有较大突释。原位凝胶内药物在体内释放主要可以分为3个阶段：突释阶段、扩散阶段和聚合物降解阶段(如图2所示)。突释阶段主要指制剂注入时有机溶剂与组织液接触发生相分离，从而导致药物的迅速释放。大量研究表明，这一阶段药物释放量可至8％-95％之间。对于帕金森病、阿尔兹海默症、精神分裂症等中枢神经系统疾病而言，治疗的药物通常安全窗窄，需要严格控制血药浓度波动范围，而药物突释往往会导致药物体内暴露量迅速增加，进而导致严重的毒副作用。
因此，如何解决
Figure PCTCN2022138871-appb-000009
中药物的突释，得到一种可持续稳定释放一周、一月甚至更长时间的制剂，是目前亟需解决的主要难题。
发明内容
发明要解决的问题
针对
Figure PCTCN2022138871-appb-000010
原位凝胶制剂药物在体内的突释阶段释放量较大的问题，本公开提供了一种可平稳释放的持续性递送制剂，解决传统原位凝胶(Atrigel技术)初期突释较大的难题。
用于解决问题的方案
[1].一种递送制剂，其包含活性药物成分和凝胶载体，其中，凝胶载体包含生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料。
[2].根据[1]所述的递送制剂，其特征在于，所述疏水添加剂选自乙酸乙酯、中链甘油三酯、三乙酸甘油酯、三辛酸甘油酯、苯甲酸苄酯和苯甲醇中的一种或多种；优选地，所述疏水添加剂选自苯甲酸苄酯、三乙酸甘油酯和三辛酸甘油酯中的一种或多种。
[3].根据[1]或[2]所述的递送制剂，其特征在于，所述疏水添加剂占所述凝胶载体总质量的1％-50％，优选地占所述凝胶载体总质量的5％-30％。
[4].根据[1]至[3]中任一项所述的递送制剂，其特征在于，所述亲水凝胶骨架材料选自泊洛沙姆、卡波姆、聚乙烯吡咯烷酮、羟丙基甲基纤维素和羧甲基纤维素钠中的一种或多种；优选地，所述亲水凝胶骨架材料选自泊洛沙姆188、卡波姆和聚乙烯吡咯烷酮中的一种或多种。
[5].根据[1]至[4]中任一项所述的递送制剂，其特征在于，若存在，所述亲水凝胶骨架材料占所述凝胶载体总质量的0.5％-15％，优选地占所述凝胶载体总质量的1％-5％。
[6].根据[1]至[5]中任一项所述的递送制剂，其特征在于，所述生物可降解聚合物选自聚酯或聚酯共聚物；优选地，所述生物可降解聚合物选自聚丙交酯或丙交酯/乙交酯共聚物；优选地，所述生物可降解聚合物选自丙交酯/乙交酯共聚物；更优选地，所述丙交酯/乙交酯共聚物中丙交酯与乙交酯摩尔比为50:50-95:5；和/或所述生物可降解聚合物的分子量为5000-70000Da；和/或所述生物可降解聚合物占所述凝胶载体总质量的20％-50％。
[7].根据[1]至[6]中任一项所述的递送制剂，其特征在于，所述有机溶剂为N-甲基吡咯烷酮和/或二甲基亚砜；和/或所述有机溶剂与所述疏水添加剂的质量比为1:1-9:1。
[8].根据[1]至[7]中任一项所述的递送制剂，其特征在于，所述活性药物成分占所述递送制剂总质量的0.5％-30％；优选地，所述活性药物成分占所述递送制剂总质量的3％-20％。
[9].一种根据[1]至[8]中任一项所述的递送制剂的制备方法，其包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，加入活性药物成分，混合至均一，即得。
[10].根据[9]所述的制备方法，其特征在于，所述活性药物成分在所述递送制剂临用前加入。
[11].根据[9]所述的制备方法，其特征在于，所述活性药物成分在所述生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料混合至均一后立即加入。
[12].一种根据[1]至[8]中任一项所述的递送制剂的制备方法，其包括如下步骤：取处方量的生物可降解聚合物、活性药物成分、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，即得。
发明的效果
本公开提供了一种可平稳释放的持续性递送制剂，相比传统Atrigel技术制备的原位凝胶，在添加少量疏水添加剂和任选的亲水凝胶骨架材料后，具有明显的减缓药物体内外突释的效果，且体内血药浓度在安全有效范围内可维持超过一周。同时上述制剂制备方法简单，适于规模化生产。并且，成品递送制剂具有使用上的便利性。
附图说明
图1为
Figure PCTCN2022138871-appb-000011
产品的组成示意图。
图2为
Figure PCTCN2022138871-appb-000012
产品的释放机理示意图。
图3为本公开递送制剂的组成示意图。
图4为实施例5、10、11、12中样品在大鼠体内的504h内的药物浓度vs时间曲线。
图5为实施例13、14、15中样品在大鼠体内的240h内的药物浓度vs时间曲线。
图6为实施例28中样品在大鼠体内的312h内的药物浓度vs时间曲线。
图7为实施例1、3、5中样品在大鼠体内的504h内的药物浓度vs时间曲线。
图8为实施例10、11、12中样品在大鼠体内的504h内的药物浓度vs时间曲线。
图9为实施例13、14中样品在大鼠体内的720h内的药物浓度vs时间曲线。
图10为实施例15、16、29、30中样品在大鼠体内的720h内的药物浓度vs时间曲线。
具体实施方式
以下对本公开的实施方式进行说明，但本公开不限定于此。本公开不限于以下说明的各构成，在请求保护的范围内可以进行各种变更，而适当组合不同实施方式、实施例中各自公开的技术手段而得 到的实施方式、实施例也包含在本公开的技术范围中。
除非另有定义，本公开所用的技术和科学术语具有与本公开所属技术领域中的普通技术人员所通常理解的相同含义。
在本公开中，使用“数值A～数值B”或“数值A-数值B”表示的数值范围是指包含端点数值A、B的范围。
在本公开中，使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。本说明书中，“任选的”或“任选地”是指接下来描述的事件或情况可发生或可不发生，并且该描述包括该事件发生的情况和该事件不发生的情况。
在本公开中，术语“一(a)”或“一(an)”或“一(the)”可以指“一个”，也可以指“一个或多个”、“至少一个”以及“一个或多于一个”。
在本公开中，术语“约”可以表示：一个值包括测定该值所使用的装置或方法的误差的标准偏差。用以界定本公开的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因前述测试装置或方法所致的标准偏差。因此，除非另有明确的说明，应当理解本公开所用的所有范围、数量、数值与百分比均经过“约”的修饰。在此处，“约”通常是指实际数值在某一特定数值或范围的±10％、±5％、±1％或±0.5％之内。
在本公开中，关于PLGA的参数问题做出如下解释：以PLGA(7525 DLG 2A)为示例，“7525”表示丙交酯与乙交酯摩尔比为75:25；“DLG”表示丙交酯/乙交酯共聚物，若为“DL”表示聚丙交酯；“2”为特性粘度标识，其中1表示特性粘度为0.05-0.15dL/g，1.5表示特性粘度为0.10-0.20dL/g，2表示特性粘度为0.15-0.25dL/g，2.5表示特性粘度为0.20-0.30dL/g，3表示特性粘度为0.25-0.35dL/g，3.5表示特性粘度为0.30-0.40dL/g，4表示特性粘度为0.35-0.45dL/g，4.5表示特性粘度为0.40-0.50dL/g，5表示特性粘度为0.45-0.55dL/g，6表示特性粘度为0.50-0.70dL/g，7表示特性粘度为0.60-0.80dL/g，8表示特性粘度为0.70-0.90dL/g，9表示特性粘度为0.80-1.00dL/g；分子量为100000Da的PLGA对应的特性粘度为1dL/g；“A”表示端基为酸，若为“E”表示端基为酯。
<第一方面>
本公开在第一方面中提供了一种凝胶载体，其包含生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料。
[凝胶载体]
在本公开中，“凝胶载体”是指用于包裹、递送和/或释放生物活性剂或活性药物成分的一种物质或多种物质的组合物，例如包含生物可降解聚合物和有机溶剂。
在一些具体的实施方式中，本公开的凝胶载体包含生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料。在一些更具体的实施方式中，本公开的凝胶载体包含生物可降解聚合物、有机溶剂和疏水添加剂。在另一些更具体的实施方式中，本公开的凝胶载体包含生物可降解聚合物、有机溶剂、疏水添加剂和亲水凝胶骨架材料。
[生物可降解聚合物]
在本公开中，“生物可降解聚合物”、“生物可吸收聚合物”和“可吸收聚合物”可互换使用，是指在与生理环境相互作用时，可通过化学或物理方法分解的聚合物，例如在受试者内的植入部位，在一段时间内，例如在几天，几周或几个月内侵蚀，分解或溶解。生物可降解聚合物在受试者中起到暂时的作用，例如递送生物活性剂如药物。生物可降解聚合物可降解成碎片并被宿主代谢或排泄。本公开对生物可降解聚合物的具体种类不做特别限定，可由所属领域技术人员根据实际需要而确定。
在本公开中，生物可降解聚合物可以是聚酯，其是指其中所有或基本上所有重复单元通过酯基连接在一起的聚合物。聚酯可以通过使具有羧基和羟基的单体反应以形成酯基而形成。聚酯可以通过环状酯单体的开环聚合形成。聚酯可以由单体如乙交酯，丙交酯，ε-己内酯或对二氧六环酮形成。在一些具体的实施方式中，本公开的生物可降解聚合物选自聚丙交酯。
在本公开中，生物可降解聚合物可以是可吸收聚酯共聚物，三聚物，四聚物或其混合物。合适的可吸收聚酯共聚物包括但不限于丙交酯/乙交酯共聚物，ε-己内酯/乙交酯共聚物，丙交酯/碳酸三亚甲 基酯共聚物，丙交酯/乙交酯/己内酯三元共聚物，丙交酯/乙交酯/碳酸三亚甲基酯三元共聚物，丙交酯/己内酯/碳酸三亚甲基酯三元共聚物，乙交酯/己内酯/碳酸三亚甲基酯三元共聚物，以及丙交酯/乙交酯/己内酯/碳酸三亚甲基酯四元共聚物。
在一些具体的实施方式中，本公开的生物可降解聚合物选自丙交酯/乙交酯共聚物(聚乳酸-羟基乙酸共聚物)。在一些更具体的实施方式中，本公开所使用的丙交酯/乙交酯共聚物中的丙交酯与乙交酯的摩尔比为50:50-95:5；示例性的，具体可以为50:50、75:25、85:15或95:5等。
本公开对生物可降解聚合物的分子量大小不做特别限定，本领域技术人员可根据实际需要确定。在一些具体的实施方式中，本公开的生物可降解聚合物的分子量为5000-70000Da，优选为10000-50000Da；示例性的，具体可以为5000Da、10000Da、15000Da、20000Da、25000Da、30000Da、35000Da、40000Da、45000Da、50000Da、55000Da、60000Da、65000Da、70000Da或所述范围内的任意数值等。
在本公开中，生物可降解聚合物的含量可以根据具体需要在一定范围内进行调整。在一些具体的实施方式中，本公开的生物可降解聚合物的含量以质量百分比计占凝胶载体总质量的20％-50％；示例性的，具体可以为20％、23％、25％、27％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％或50％等。在一些更具体的实施方式中，本公开的生物可降解聚合物的含量以质量百分比计占凝胶载体总质量的30％-50％。
在本公开中，生物可降解聚合物还可以是聚醚酯，其指其中所有或基本上所有重复单元通过酯基或醚基连接在一起的聚合物，并且其中醚基和酯基都作为连接基团存在于聚合物中。生物可降解聚合物可以是聚醚/聚酯聚合物，其是一种具有嵌段共聚物结构的聚醚酯，该嵌段共聚物结构包括通过醚基连接在一起的一个或多个重复单元嵌段和通过酯基连接在一起的一个或多个重复单元嵌段。
[有机溶剂]
在本公开中，“有机溶剂”是指生物相容性有机溶剂，其可在生物体内进行扩散，被生物体代谢或吸收。例如本领域中的N-甲基吡咯烷酮、乙酸乙酯、中链甘油三酯、三乙酸甘油酯、三辛酸甘油酯、苯甲酸苄酯、苯甲醇、二甲基亚砜、苯甲酸乙酯、乙醇、甘油糖醛和甘油缩甲醛等。
在一些具体的实施方式中，本公开的有机溶剂为N-甲基吡咯烷酮和/或二甲基亚砜。在一些具体的实施方式中，本公开的有机溶剂为N-甲基吡咯烷酮。在另一些具体的实施方式中，本公开的有机溶剂为二甲基亚砜。在一些具体的实施方式中，本公开的有机溶剂为N-甲基吡咯烷酮和二甲基亚砜。
在本公开中，有机溶剂的含量可以根据具体需要在一定范围内进行调整。在一些具体的实施方式中，本公开的有机溶剂与疏水添加剂的质量比为1:1-9:1；示例性的，具体可以为1:1、2:1、3:1、4:1、5:1、6:1、7:1、7:3、8:1或9:1等。在一些具体的实施方式中，本公开的有机溶剂的含量以质量百分比计占凝胶载体总质量的20％-60％；示例性的，具体可以为20％、25％、30％、35％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％或60％等。
[疏水添加剂]
在本公开中，“疏水性添加剂”可以是具有疏水性的药学上可接受的添加剂，并且不包括疏水性活性物质或活性成分。例如本领域中的脂肪醇如硬脂醇、脂肪酸如山梨酸、脂肪酸酯如中链甘油三酯、硅氧烷化合物如二甲基硅氧烷等。
在一些具体的实施方案中，本公开的疏水添加剂选自乙酸乙酯、中链甘油三酯、三乙酸甘油酯、三辛酸甘油酯、苯甲酸苄酯和苯甲醇中的一种或多种。在一些具体的实施方案中，本公开的疏水添加剂选自三乙酸甘油酯、三辛酸甘油酯和苯甲酸苄酯中的一种或多种。
在本公开中，疏水添加剂的含量可以根据具体需要在一定范围内进行调整。在一些具体的实施方式中，本公开的疏水添加剂的含量以质量百分比计占凝胶载体总质量的1％-50％；示例性的，具体可以为1％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、30％、35％、40％、45％或50％等。在一些更具体的实施方式中，本公开的疏水添加剂的含量以质量百分比计占凝胶载体总质量的5％-30％。
[亲水凝胶骨架材料]
在本公开中，“亲水凝胶骨架材料”是作为载体材料的一种辅料，主要是调节药物释放速率，起缓释、控释作用，使制剂中药物释放速率和释放量达到适当的要求，确保药物以一定的速率输送到病患部位，并在体内维持一定浓度，获得预期的效果，减小毒副作用。
在一些具体的实施方式中，本公开的凝胶载体包含亲水凝胶骨架材料。在另一些具体的实施方式中，本公开的凝胶载体不包含亲水凝胶骨架材料。
在本公开中，亲水凝胶骨架材料可以为亲水性聚合物，例如天然胶，如海藻酸盐、琼脂、黄原胶、西黄蓍胶等；纤维素衍生物，如甲基纤维素(MC)、羧甲基纤维素钠(CMC-Na)、羟丙甲纤维素(HPMC)、羟乙基纤维素(HEC)等；非纤维素多糖类，如甲壳素、壳聚糖、卡波姆等；高分子聚合物，如聚维酮(PVP)、乙烯聚合物、丙烯酸树脂、聚乙烯醇(PVA)等。
在一些具体的实施方式中，本公开的亲水凝胶骨架材料选自泊洛沙姆、卡波姆、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羧甲基纤维素钠中的一种或多种。在一些更具体的实施方式中，本公开的亲水凝胶骨架材料选自泊洛沙姆188、卡波姆和聚乙烯吡咯烷酮中的一种或多种。
在本公开中，亲水凝胶骨架材料的含量可以根据具体需要在一定范围内进行调整。在一些具体的实施方案中，本公开的亲水凝胶骨架材料的含量以质量百分比计占凝胶载体总质量的0.5％-15％；示例性的，具体可以为0.5％、1％、2％、3％、4％、5％、7％、10％、12％或15％等。在一些更具体的实施方案中，本公开的亲水凝胶骨架材料的含量以质量百分比计占凝胶载体总质量的1％-5％。
<第二方面>
本公开在第二方面中提供了一种递送制剂，其包含活性药物成分和本公开在上述<第一方面>中提供的凝胶载体。
在本方面所使用或出现的术语，如果在<第一方面>部分有公开，则与上述部分中的公开或定义具有相同的含义。
[递送制剂]
在本公开中，“递送制剂”是一种药物组合物，其含有活性药物成分(API)和凝胶载体(在某些情况下，其仅含有活性药物成分和凝胶载体)，其施予受试者后可以以特定的释放行为(例如，平稳、缓慢并持续地)释放活性药物成分。
在一些具体的实施方式中，本公开的递送制剂包含活性药物成分和凝胶载体，其中，凝胶载体包含生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料。在一些更具体的实施方式中，本公开的递送制剂包含活性药物成分、生物可降解聚合物、有机溶剂和疏水添加剂。在另一些更具体的实施方式中，本公开的递送制剂包含活性药物成分、生物可降解聚合物、有机溶剂、疏水添加剂和亲水凝胶骨架材料。
[活性药物成分]
在本公开中，“活性药物成分”是指在递送制剂中的任何一种物质或物质的混合物，此种物质在疾病的诊断、治疗、症状缓解、处理或疾病的预防中有药理活性或其他直接作用或者能影响机体的功能或结构。
在一些实施方式中，本公开的活性药物成分可以选自治疗精神分裂的药物或激素类药物。在一些具体的实施方式中，本公开的活性药物成分包括但不限于利培酮、帕利哌酮、布比卡因、罗哌卡因、亮丙瑞林、曲谱瑞林、奥曲肽、罗替高汀、普拉克索、卢美哌隆或其药学上可接受的盐等。在一些具体的实施方式中，本公开的活性药物成分选自罗替高汀、普拉克索、卢美哌隆或其药学上可接受的盐等。
在本公开中，活性药物成分的含量可以根据具体需要在一定范围内进行调整。在一些具体的实施方式中，活性药物成分的含量均以其游离碱形式进行计算。在另一些具体的实施方式中，活性药物成分的含量均以其酸加成盐形式进行计算。在一些具体的实施方式中，本公开的递送制剂中的活性药物成分的含量(例如，以其游离碱形式进行计算)以质量百分比计为0.5％-30％；示例性的，具体可以为0.5％、1％、2％、3％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、4％、4.1％、 4.2％、4.3％、4.4％、4.5％、5％、5.1％、5.2％、5.3％、5.4％、5.5％、6％、6.1％、6.2％、6.3％、6.4％、6.5％、6.6％、6.7％、6.8％、6.9％、7％、7.1％、7.2％、7.3％、7.4％、7.5％、8％、8.5％、9％、9.1％、9.2％、9.3％、9.4％、9.5％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％或30％等。在一些更具体的实施方式中，本公开的递送制剂中的活性药物成分的含量(例如，以其游离碱形式进行计算)以质量百分比计为3％-20％。
<第三方面>
本公开在第三方面中提供了本公开在上述<第一方面>中提供的凝胶载体的制备方法。
在本方面所使用或出现的术语，如果在<第一方面>部分有公开，则与上述部分中的公开或定义具有相同的含义。
在一些具体的实施方式中，本公开的凝胶载体的制备方法可以包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，即得。
<第四方面>
本公开在第四方面中提供了本公开在上述<第二方面>中提供的递送制剂的制备方法。
在本方面所使用或出现的术语，如果在<第一方面>或<第二方面>部分有公开，则与上述部分中的公开或定义具有相同的含义。
在一些具体的实施方式中，本公开的递送制剂的制备方法可以包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，然后加入活性药物成分(例如，处方量的活性药物成分)，混合至均一，即得。
在一些优选的实施方式中，本公开的递送制剂的制备方法可以包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，临用前，加入活性药物成分(例如，处方量的活性药物成分)，混合至均一，即得。在此实施方案中，待临用前再加入活性药物，有助于保证递送制剂的稳定性。
在另一些优选的实施方式中，本公开的递送制剂的制备方法可以包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，立即加入活性药物成分(例如，处方量的活性药物成分)，混合至均一，即得。在此实施方案中，不必待临用前再加入活性药物，制备得到的含有活性药物的递送制剂可以稳定储存，同时提高了递送试剂使用时的便利性。
在另一些具体的实施方式中，本公开的递送制剂的制备方法可以包括如下步骤：取处方量的生物可降解聚合物、活性药物成分、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，即得。在此实施方案中，不需要提前将凝胶载体成分溶解混合，其可直接与活性药物成分一起混合至均一，从而不必考虑各成分的溶解顺序及活性药物成分的添加时机，同时也不会对递送制剂储存过程中的稳定性带来负面影响，极大的提高了递送试剂储存、运输和使用时的便利性。
本公开的递送制剂的组成如图3所示，为更清楚地表述本公开的技术方案，下面结合具体实施例进一步说明，但不能用于限制本公开，此仅是本公开的部分实施例。除非另有说明，本公开中使用的仪器、试剂、材料、实验动物等均可通过常规商业手段获得。
实施例1
精密称取0.490g PLGA(7525 DLG 2A)，0.210g PLGA(5050 DLG 4.5A)，加入1.060g NMP搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例2
精密称取0.490g PLGA(7525 DLG 2A)，0.210g PLGA(5050 DLG 4.5A)，加入0.954g NMP、0.106g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例3
精密称取0.490g PLGA(7525 DLG 2A)，0.210g PLGA(5050 DLG 4.5A)，加入0.848g NMP、0.212g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例4
精密称取0.490g PLGA(7525 DLG 2A)，0.210g PLGA(5050 DLG 4.5A)，加入0.848g NMP、0.212g三辛酸甘油酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例5
精密称取0.490g PLGA(7525 DLG 2A)，0.210g PLGA(5050 DLG 4.5A)，加入0.848g NMP、0.212g三乙酸甘油酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例6
精密称取0.572g PLGA(5050 DLG 4.5A)，加入0.954g NMP、0.106g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例7
精密称取0.572g PLGA(5050 DLG 4.5A)，0.088g泊洛沙姆188，加入0.954g NMP、0.106g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例8
精密称取0.572g PLGA(5050 DLG 4.5A)，0.088g聚乙烯吡咯烷酮，加入0.954g NMP、0.106g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例9
精密称取0.572g PLGA(5050 DLG 4.5A)，0.018g卡波姆，加入0.954g NMP、0.106g苯甲酸苄酯搅拌溶解，得到澄清透明凝胶溶液。临用前向上述制备的溶液中加入0.120g罗替高汀，混合至均一，即得。
实施例10
精密称取0.525g PLGA(5050 DLG 2E)，加入0.555g NMP、0.240g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.090g罗替高汀，混合至均一，即得。
实施例11
精密称取0.345g PLGA(5050 DLG 4.5A)，加入0.555g NMP、0.240g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.090g罗替高汀，混合至均一，即得。
实施例12
精密称取0.345g PLGA(7525 DLG 5.5E)，加入0.555g NMP、0.240g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.090g罗替高汀，混合至均一，即得。
实施例13
精密称取0.525g PLGA(5050 DLG 4.5A)，加入0.683g NMP、0.293g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例14
精密称取0.525g PLGA(7525 DLG 5.5E)，加入0.683g NMP、0.293g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例15
精密称取0.675g PLGA(7525 DLG 2A)，加入0.578g NMP、0.248g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例16
精密称取0.675g PLGA(100 DL 2A)，加入0.578g NMP、0.248g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例17
精密称取0.245g PLGA(7525 DLG 2A)和0.105g PLGA(5050 DLG 4.5A)，加入0.477g NMP与0.053g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.090g普拉克索，混合至均一，即得。
实施例18
精密称取0.245g PLGA(7525 DLG 2A)和0.105g PLGA(5050 DLG 4.5A)，加入0.477g NMP与0.053g三乙酸甘油酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.090g普拉克索，混合至均一，即得。
实施例19
精密称取0.540g PLGA(5050 DLG 2E)，加入0.810g NMP搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.082g普拉克索双羟萘酸盐(API:酸＝2:1)，混合至均一，即得。
实施例20
精密称取0.572g PLGA(5050 DLG 2E)，0.088g泊洛沙姆188，加入0.954g NMP与0.106g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.108g普拉克索双羟萘酸盐(API:酸＝2:1)，混合至均一，即得。
实施例21
精密称取0.540g PLGA(5050 DLG 2E)，加入0.810g NMP搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.120g普拉克索双羟萘酸盐(API:酸＝1:1)，混合至均一，即得。
实施例22
精密称取0.572g PLGA(5050 DLG 2E)，0.088g聚乙烯吡咯烷酮，加入0.954g NMP与0.106g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.156g普拉克索双羟萘酸盐(API:酸＝1:1)，混合至均一，即得。
实施例23
精密称取0.540g PLGA(5050 DLG 2E)，加入0.810g NMP搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.096g普拉克索棕榈酸盐，混合至均一，即得。
实施例24
精密称取0.572g PLGA(5050 DLG 2E)，0.018g卡波姆，加入0.954g NMP与0.106g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.118g普拉克索棕榈酸盐，混合至均一，即得。
实施例25
精密称取0.350g PLGA(5050 DLG 4.5A)，加入0.477g NMP搅拌至溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.220g卢美哌隆，混合至均一，即得。
实施例26
精密称取0.350g PLGA(5050 DLG 4.5A)，加入0.477g NMP、0.053g三乙酸甘油酯搅拌至溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.220g卢美哌隆，混合至均一，即得。
实施例27
精密称取0.213g PLGA(5050 DLG 4.5A)、0.491g PLGA(7525 DLG 2A)，加入0.965g NMP、0.104g三乙酸甘油酯搅拌至溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.438g卢美哌隆，混合至均一，即得。
实施例28
精密称取0.210g PLGA(5050 DLG 4.5A)、0.490g PLGA(7525 DLG 2A)，加入0.954g NMP、0.106g三乙酸甘油酯搅拌至溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.142g卢美哌隆混合至均一，即得。
实施例29
精密称取0.675g PLGA(7525 DLG 2A)，加入0.826g NMP搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例30
精密称取0.675g PLGA(8515 DLG 2A)，加入0.578g NMP、0.248g苯甲酸苄酯搅拌溶解，得到澄清透明溶液。临用前向上述制备的溶液中加入0.055g罗替高汀，混合至均一，即得。
实施例31
精密称取0.675g PLGA(7525 DLG 2A)，加入0.578g NMP、0.248g苯甲酸苄酯搅拌溶解，得到澄清透明溶液后加入0.055g罗替高汀，混合至均一，即得。
实施例32
精密称取0.675g PLGA(7525 DLG 2A)、0.578g NMP、0.248g苯甲酸苄酯、0.055g罗替高汀搅拌混合溶解至均一，即得。
上述实施例处方组成如下表1所示：
表1 实施例处方组成列表
Figure PCTCN2022138871-appb-000013
Figure PCTCN2022138871-appb-000014
Figure PCTCN2022138871-appb-000015
备注： 1,2,3疏水添加剂含量、亲水凝胶骨架材料、PLGA含量均为各自占凝胶载体中的重量比(不含API)；
4载药量为API占总制剂的质量比(含API)，其中普拉克索双羟萘酸盐、普拉克索棕榈酸盐等盐形式均以游离碱形式进行折算。
实验例1：原位凝胶制剂粘度考察
参照《中国药典》四部通则0633第三法。选用锥形数字粘度计测定。精密量取样品溶液500μL，选用40号转子或选用52号转子，于25℃测定，调节转数，使扭矩在25％～75％范围内。每个样品平行测试两次，测得粘度值如下表。
表2 罗替高汀原位凝胶粘度考察结果
  PLGA浓度(％) PLGA种类 温度(℃) 粘度(CP)
实施例10 40 5050 DLG 2E 25 1851
实施例11 30 5050 DLG 4.5A 25 6349
实施例12 30 7525 DLG 5.5E 25 7756
实施例13 35 5050 DLG 4.5A 25 17865
实施例14 35 7525 DLG 5.5E 25 19409
实施例15 45 7525 DLG 2A 25 1988
实施例29 45 7525 DLG 2A 25 1156
实施例10-15、29结果显示，制剂粘度主要与PLGA分子量及浓度相关，PLGA分子量或浓度越大，制剂粘度越大；另外，疏水添加剂也会使制剂黏度增大。结合释放结果可知，相同情况下，制剂粘度越大，药物体外释放越慢，其主要原因可能为粘度增加使凝胶载体更加致密，增加了载体对药物的阻力，致使外部介质较难进入凝胶骨架，PLGA降解减慢，从而使释放减慢。制剂载药量相同或相近时，凝胶粘度和聚合物中丙交酯：乙交酯比例均会影响药物缓释效果。
实验例2：原位凝胶制剂体外释放度考察
(1)罗替高汀原位凝胶制剂体外释放度考察
使用1mL注射器连接21G针头(外径0.8mm)，吸取0.1mL，精密称重。将样品缓慢推注到释放介质(0.01M磷酸盐缓冲溶液(含0.02％NaN 3，0.2％SDS，pH调节至7.40))，释放介质体积根据漏槽条件进行调整，再次精密称取注射器，减重法计算注入样品量。样品瓶放入37±0.5℃恒温振荡水槽中，50rpm振荡。每个样品平行制备三份。在预定时间点取上清液2mL，同时补充相同温度释放介质2mL。取上述供试液用HPLC检测，按外标法计算累积释放量。
(2)普拉克索原位凝胶制剂体外释放度考察
使用1mL注射器连接21G针头(外径0.8mm)，吸取0.1mL，精密称重。将制剂缓慢推注到释放介质(0.01M磷酸盐缓冲溶液(含0.02％NaN 3，0.2％SDS，pH调节至7.40))，释放介质体积根据漏槽条件进行调整，再次精密称取注射器，减重法计算注入样品量。样品瓶放入37±0.5℃恒温振荡水槽中，50rpm振荡。每个样品平行制备三份。在预定时间点取上清液2mL，同时补充相同温度释放介质2mL。取上述供试液用HPLC检测，按外标法计算累积释放量。
(3)卢美哌隆原位凝胶制剂体外释放度考察
使用1mL注射器连接21G针头(外径0.8mm)，吸取0.04mL，精密称重。将制剂缓慢推注到释放介质(0.01M磷酸盐缓冲溶液(含0.02％NaN 3，0.2％SDS，pH调节至7.40))，释放介质体积根据漏槽条件进行调整，再次精密称取注射器，减重法计算注入样品量。样品瓶放入37±0.5℃恒温振荡水槽中，50rpm振荡。每个样品平行制备三份。在预定时间点取上清液2mL，同时补充相同温度释放介质2mL。取上述供试液用HPLC检测，按外标法计算累积释放量。
表3 部分实施例制剂体外释放度考察结果
Figure PCTCN2022138871-appb-000016
实施例1-5中，与实施例1相比，实施例2-5添加一定比例的疏水性添加剂如苯甲酸苄酯、三乙酸甘油酯或三辛酸甘油酯后，制剂1h/24h突释显著降低。实施例6-9中，与实施例6相比，实施例7-9加入少量亲水凝胶骨架材料后，1h突释明显降低。实施例10-12，筛选不同种类PLGA对制剂释放度的影响，5050 DLG 4.5A组制剂24h突释较小，而释放周期主要与聚合物分子量大小相关，随分子量增大而显著延长，5050 DLG 4.5A、7525 DLG 5.5E组制剂较5050 2E组释放周期显著延长，其中7525 DLG 5.5E释放周期最长。实施例13-16、29和30，与实施例10-12比较，降低载药量的同时提高PLGA浓度，进一步筛选不同PLGA最佳处方组合，结果显示制剂体外1h/24h突释较前述实施例增加。疏水添加剂可显著降低突释，但不同种类的PLGA对突释影响不同，聚合物分子量、丙交酯乙交酯比例均会影响突释效果。实施例19-24中，与实施例19、21、23相比，对应的实施例20、22、24加入一定比例的疏水性 添加剂和亲水凝胶骨架材料后，药物1h/24h突释显著降低，且释放周期延长，体内血药浓度在安全有效范围内可维持超过一周。实施例25-28中，与实施例25相比，实施例26-28加入一定疏水性添加剂后，1h/24h突释降低。
实验例3：原位凝胶制剂在大鼠体内释放度考察
(1)罗替高汀原位凝胶制剂大鼠体内释放度考察
选择SD雄性大鼠(N＝5)考察体内非线性药代动力学(PK)行为。给药剂量为10mg/kg(以罗替高汀计)，皮下注射上述部分实施例中的制剂，在预定时间点尾静脉取血，血浆样品经SPE(Solid-Phase Extraction)处理后，采用LC-MS/MS法测定罗替高汀浓度。实施例5、10～12样品在大鼠体内药物浓度随时间(504h内)变化曲线如图4所示。实施例1、3、5样品在大鼠体内药物浓度随时间(504h内)变化曲线如图7所示，实施例10-12样品在大鼠体内药物浓度随时间(504h内)变化曲线如图8所示。
表4 罗替高汀原位凝胶大鼠体内血药浓度(实施例1、3、5、10-12)
Figure PCTCN2022138871-appb-000017
(2)罗替高汀原位凝胶制剂大鼠体内释放度考察
选择SD雄性大鼠(N＝5)考察体内PK行为。给药剂量为5mg/kg(以罗替高汀计)，皮下注射上述部分实施例中的制剂，在预定时间点尾静脉取血，血浆样品经SPE(Solid-Phase Extraction)处理后，采用LC-MS/MS法测定罗替高汀浓度。实施例13-14样品在大鼠体内药物浓度随时间(720h内)变化曲线如图9所示，实施例15-16、29和30样品在大鼠体内药物浓度随时间(720h内)变化曲线如图10所示。实施例13-15样品在大鼠体内药物浓度随时间(240h内)变化曲线如图5所示。
表5 罗替高汀原位凝胶大鼠体内血药浓度(实施例13-16、29-30)
Figure PCTCN2022138871-appb-000018
(3)卢美哌隆原位凝胶制剂大鼠体内释放度考察
选择SD雄性大鼠(N＝5)考察体内PK行为。给药剂量为10.5mg/kg(以卢美哌隆计)，皮下注射上述部分实施例中的制剂，在预定时间点尾静脉取血，血浆样品经SPE(Solid-Phase Extraction)处理后，采用LC-MS/MS法测定卢美哌隆浓度。实施例28样品在大鼠体内药物浓度随时间(312h内)变化曲线如图6所示。
表6 卢美哌隆原位凝胶大鼠体内血药浓度
Figure PCTCN2022138871-appb-000019
采用传统Atrigel技术制备的原位凝胶(活性成分为罗替高汀、普拉克索、卢美哌隆等)体外突释较大，不适用于安全治疗窗较窄的药物，当添加部分疏水添加剂(如苯甲酸苄酯、三乙酸甘油酯、三辛酸甘油酯、中链三乙酸甘油酯等)和任选的亲水凝胶骨架材料(如泊洛沙姆、羧甲基纤维素钠、卡波姆、羟丙甲基纤维素、聚乙烯吡咯烷酮等)后，具有明显的减缓体内外突释的效果，且体内血药浓度在安全有效范围内可维持超过一周。
实验例4：存储过程中罗替高汀有关物质考察
在2～8℃避光条件下放置规定时间后，称取180mg样品，置2mL容量瓶中，加入杂质对照品贮备液0.4mL，用稀释剂溶解并稀释至刻度，摇匀后采用HPLC检测罗替高汀有关物质含量，实施例15、实施例31、实施例32样品存储0天和3月有关物质含量检测结果如表7所示。
表7 不同制备方法下罗替高汀原位凝胶储存过程中的有关物质含量
Figure PCTCN2022138871-appb-000020
实施例15样品在2～8℃避光条件下存储3个月，罗替高汀有关物质种类和含量无明显变化。实施例31和32样品储存0天的杂质与实施例15样品相近，2～8℃保存3月后实施例31和实施例32样品中有部分活性成分有关物质(杂质C、E、K)含量稍有增加，但仍满足递送制剂质量要求。

Claims (12)

  1. 一种递送制剂，其包含活性药物成分和凝胶载体，其中，凝胶载体包含生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料。
  2. 根据权利要求1所述的递送制剂，其特征在于，所述疏水添加剂选自乙酸乙酯、中链甘油三酯、三乙酸甘油酯、三辛酸甘油酯、苯甲酸苄酯和苯甲醇中的一种或多种；优选地，所述疏水添加剂选自苯甲酸苄酯、三乙酸甘油酯和三辛酸甘油酯中的一种或多种。
  3. 根据权利要求1或2所述的递送制剂，其特征在于，所述疏水添加剂占所述凝胶载体总质量的1％-50％，优选地占所述凝胶载体总质量的5％-30％。
  4. 根据权利要求1至3中任一项所述的递送制剂，其特征在于，所述亲水凝胶骨架材料选自泊洛沙姆、卡波姆、聚乙烯吡咯烷酮、羟丙基甲基纤维素和羧甲基纤维素钠中的一种或多种；优选地，所述亲水凝胶骨架材料选自泊洛沙姆188、卡波姆和聚乙烯吡咯烷酮中的一种或多种。
  5. 根据权利要求1至4中任一项所述的递送制剂，其特征在于，若存在，所述亲水凝胶骨架材料占所述凝胶载体总质量的0.5％-15％，优选地占所述凝胶载体总质量的1％-5％。
  6. 根据权利要求1至5中任一项所述的递送制剂，其特征在于，所述生物可降解聚合物选自聚酯或聚酯共聚物；优选地，所述生物可降解聚合物选自聚丙交酯或丙交酯/乙交酯共聚物；优选地，所述生物可降解聚合物选自丙交酯/乙交酯共聚物；更优选地，所述丙交酯/乙交酯共聚物中丙交酯与乙交酯摩尔比为50:50-95:5；
    和/或所述生物可降解聚合物的分子量为5000-70000Da；
    和/或所述生物可降解聚合物占所述凝胶载体总质量的20％-50％。
  7. 根据权利要求1至6中任一项所述的递送制剂，其特征在于，所述有机溶剂为N-甲基吡咯烷酮和/或二甲基亚砜；和/或所述有机溶剂与所述疏水添加剂的质量比为1:1-9:1。
  8. 根据权利要求1至7中任一项所述的递送制剂，其特征在于，所述活性药物成分占所述递送制剂总质量的0.5％-30％；优选地，所述活性药物成分占所述递送制剂总质量的3％-20％。
  9. 一种根据权利要求1至8中任一项所述的递送制剂的制备方法，其包括如下步骤：取处方量的生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，加入活性药物成分，混合至均一，即得。
  10. 根据权利要求9所述的制备方法，其特征在于，所述活性药物成分在所述递送制剂临用前加入。
  11. 根据权利要求9所述的制备方法，其特征在于，所述活性药物成分在所述生物可降解聚合物、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料混合至均一后立即加入。
  12. 一种根据权利要求1至8中任一项所述的递送制剂的制备方法，其包括如下步骤：取处方量的生物可降解聚合物、活性药物成分、有机溶剂以及疏水添加剂和任选的亲水凝胶骨架材料，混合至均一，即得。
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