EP1231897A2 - Preparations de medicaments - Google Patents

Preparations de medicaments

Info

Publication number
EP1231897A2
EP1231897A2 EP00992485A EP00992485A EP1231897A2 EP 1231897 A2 EP1231897 A2 EP 1231897A2 EP 00992485 A EP00992485 A EP 00992485A EP 00992485 A EP00992485 A EP 00992485A EP 1231897 A2 EP1231897 A2 EP 1231897A2
Authority
EP
European Patent Office
Prior art keywords
hyaluronic acid
salts
aqueous solution
sustained
weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00992485A
Other languages
German (de)
English (en)
Inventor
Alan Drizen
Michael Micalizzi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LAM Pharmaceuticals LLC
Original Assignee
LAM Pharmaceuticals LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by LAM Pharmaceuticals LLC filed Critical LAM Pharmaceuticals LLC
Publication of EP1231897A2 publication Critical patent/EP1231897A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Definitions

  • This invention relates to the preparation of a transdermal delivery system.
  • the preparations is designed to deliver therapeutic levels of a drug to specific sites below the dermal level of the skin including, but not limited to, knees, ankles, hands, feet, and neck.
  • Ionic polysaccharides have been used in the application of drugs by controlled release. Such ionic polysaccharides as chitosan or sodium alginate are disclosed as useful in providing spherical agglomerates of water-insoluble drugs in the Journal of Pharmaceutical Science, Volume 78, Number 11, November 1989, Bodmeier et al. Calcium alginate gel formulations have also found use as a matrix material for the controlled release of herbicides, as disclosed in the Journal of Controlled Release, (1986) , pages 229-233, Pfister et al.
  • a molded plastic mass composed of the reaction product of a hydrophilic colloid and a cross-linking agent such as a liquid polyol, also containing an organic liquid medium such as glycerin, is disclosed as useful in the controlled release of medication or other additives.
  • the hydrophilic colloid can be carboxymethyl cellulose gum or a natural alginate gum which is cross-linked with a polyol. The cross-linking reaction is accelerated in the presence of aluminum and calcium salts.
  • compositions are disclosed for the controlled release of pharmacological macromolecular compounds contained in a matrix of chitosan.
  • Chitosan can be cross-linked utilizing aldehydes, epichlorohydrin and benzoquinone .
  • osmotic drug delivery systems are disclosed in U.S. Patent No. 4,439,196 which utilize a multi-chamber compartment for holding osmotic agents, adjuvants, enzymes, drugs, pro- drugs, pesticides, and the like. These materials are enclosed by semipermeable membranes so as to allow the fluids within the chambers to diffuse into the environment into which the osmotic drug delivery system is in contact.
  • the drug delivery can be sized for oral ingestion, implantation, rectal, vaginal, or ocular insertion for delivery of a drug or other beneficial substance.
  • over-the-counter drugs which include counter-irritants such as menthol, eucalyptus, and camphor are solid for mild relief of minor problems. These products are designed to counter-irritation and are not intended for deep penetration of tissue structures below the skin, namely into areas which include joints, ligaments, tendons and cartilage.
  • the over-the-counter drugs described above may be purchased without prescription.
  • the present invention relates a semi-solid supersaturated solution of hyaluronic acid and its salts, as well as methods of making and using these solutions to treat skin wounds. More particularly, this invention relates a method for preparing a sustained-release delivery composition which comprises dissolving hyaluronic acid and its salts in water to provide a first aqueous solution substantially saturated with hyaluronic acid and its salts; concentrating the first aqueous solution by removing between about 10 percent by weight and about 70 percent by weight of the water from said first aqueous solution, thereby converting the first aqueous solution to a semisolid, sustained-release delivery composition containing hyaluronic acid and its salts; and recovering the sustained-release delivery composition including the semisolid hyaluronic acid and its salts.
  • Another embodiment of this invention involves a semisolid supersaturated solution of hyaluronic acid and its salts having sustained drug delivery.
  • An alternative embodiment of this invention involves a method for preparing a sustained-release delivery composition which comprises dissolving hyaluronic acid and its salts in water to provide a first aqueous solution substantially saturated with hyaluronic acid and its salts; mixing the first aqueous solution with a pharmaceutically acceptable nonionic polymer to form a first viscous solution; C. removing about 10 percent to about 70 seventy percent water from the first viscous solution thereby converting the first viscous solution to a semisolid sustained-release delivery composition containing semisolid hyaluronic acid and its salts; and recovering the semisolid, sustained-release delivery composition including the hyaluronic acid and its salts.
  • An additional embodiment of this invention involves a method for preparing a sustained-release delivery composition which comprises dissolving the sodium salt of hyaluronic acid in water at about 15°C to about 40°C to provide a first aqueous solution substantially saturated with the sodium salt of hyaluronic acid; B.
  • first viscous solution mixing the first aqueous solution with a pharmaceutically acceptable viscous liquid nonionic polymer which is hydroxy ethyl cellulose to form a first viscous solution; removing water from the first viscous solution by heating the first viscous solution at a temperature between about 20°C and about 50°C until the sodium salt of hyaluronic acid in the first viscous solution is converted to the semisolid state thereby converting the first viscous solution to a semisolid, sustained-release delivery composition containing hyaluronic acid and its salts; and recovering the sustained-release delivery composition including the semisolid sodium salt of hyaluronic acid.
  • Another embodiment of this invention involves a method for treating a skin wound condition in a patient with a sustained-release drug delivery dressing which comprises a solid polymer matrix complex comprising an aqueous , ⁇ iller, ,-, « -, « O 01/39725
  • aqueous solution comprises hyaluronic acid and its salts in water; and wherein the sheet of hyaluronic acid is a concentrate of the aqueous solution.
  • An alternative embodiment of this invention involves a method for treating a skin wound condition in a patient with a sustained-release drug delivery dressing which comprises applying a formable, flexible and moveable sheet of hyaluronic and its salts to the area of the skin wound condition; securing the formable, flexible and movable sheet to said area with a layer of dressing fixative; and wherein the sheet of hyaluronic acid is a concentrate of the aqueous solution.
  • An additional embodiment of this invention involves a method for making a sustained-release drug delivery dressing skin wound dressing with a which comprises dissolving hyaluronic acid and its salts in water to provide a first aqueous solution substantially saturated with hyaluronic acid and its salts; concentrating the first aqueous solution by removing between about 10 percent by weight and about 70 percent by weight of the water from said first aqueous solution, thereby converting the first aqueous solution to a semisolid, sustained-release delivery composition containing hyaluronic acid and its salts; recovering the sustained-release delivery composition including the semisolid hyaluronic acid and its salts; further concentrating the sustained-release delivery system by spreading said delivery system into a dressing mold and further removing about 1 percent by weight to about 20 percent by weight of the water from the sustained-release delivery system; and wherein the further concentration of the sustained-release delivery dressing results in a formable, flexible and moveable sheet of hyaluronic and its salts .
  • an effective therapeutically level of a drug may be administered topically and transdermally delivered through the skin into various sites where the drug is therapeutically effective.
  • the active drug must be suspended or entrapped in a specially designed polymer matrix containing a specific molar ratio of negatively charged polymers and a non-ionic polymer suspended or dissolved in water and solubilizers .
  • This system is believed to form a matrix which microencapsulates, suspends and/or entraps the active drug entity such that when it is administered, it is slowly released into the systemic circulatory systems or muscular tissue providing a method of delivering an active to an affected site in the body through the skin.
  • the molar ratio of the polymers present in the matrix is critical in this invention. It has been found that molar ratios of the negatively charged polymer to the nonionic polymer must be from 1:0.5 to 4, and preferably from 1:0.5 to 2.0, and most preferably from 1:0.7 to 2.5.
  • At least one of the polymers used to form the matrix of this invention must be sufficiently negatively charged to aid in the dispersion, encapsulation or solubilization of the drug.
  • Particularly preferred polymers which have average molecular weights below about 800,000 and preferably molecular weights between 650,000 to 800,000 have been found acceptable to form usable polymer matrixes for transdermal delivery. Polymer with mean average molecular weights between 700,000 and 775,000 are most preferred. Polymers having molecular weights have about 800,000 form solid gels in solution and are unable to serve as part of a transdermal delivery system.
  • the polymers must be sterilizable and be stable during sterilization so that the polymer does not lose molecular weight once formulated into the final transdermal delivery form.
  • Exemplary, non-limiting examples of compounds that may be used as a source of this molecular weight polymer include polysulfated glucosoglycans, glucosaminoglycans, and mucopolysaccharides, derivatives thereof and mixtures thereof. Particularly preferred mucopolysaccharides are chondroitin sulfate and hyaluronic acid salts. Exemplary hyaluronate salts include sodium, calcium, potassium and magnesium salts with hyaluronate sodium being most preferred.
  • Hyaluronic acid occurs naturally in joint synovial fluid, where it plays a lubricating role, and may have biological activity was well.
  • HA is a mucopolysaccharide, and may alternatively be referred to as a glycosaminoglycan.
  • the repeating unit of the hyaluronic acid molecule is a disaccharide consisting of D-glucuronic acid and N-acetyl-D-glucosamine . Because hyaluronic acid possesses a negative charge at neutral pH, it is soluble in water, where it forms highly viscous solutions.
  • the D- glucuronic acid unit and N-acetyl-D-glucosamine unit are bonded through a glycosidic, beta (1-3) linkage, while each disaccharide unit is bonded to the next disaccharide unit through a beta (1-5) linkage.
  • the beta (1-4) linkages may be broken through hydrolysis with the enzyme hyaluronidase .
  • hyaluronic acid A variety of substances, commonly referred to as hyaluronic acid, have been isolated by numerous methods from various tissue sources including umbilical cords, skin, vitreous humour, synovial fluid, tumors, haemolytic streptocci pigskin, rooster combs, and the walls of veins and arteries.
  • U.S. Patent No. 2,585,546 to Hadian discloses an example of a method for obtaining hyaluronic acid which involves extracting acetone-washed umbilical cords with a dilute salt solution, acidifying the resulting extract, removing the colt so formed, precipitating some hyaluronic acid with protein from the acidified extract with ammonium sulfate, agitating the liquid with pyridine, precipitating another fraction highly contaminated with protein, followed by more ammonium sulfate which forces some pyridine out of solution along with the high viscosity hyaluronic acid.
  • the hyaluronic acid collects at the interface between the two liquid phases and may be separated by filtration, centrifugation or another usual procedure.
  • a modification of this process involves the fractionation of the acidic salt extract from the umbilical cords with alcohol and ammonium sulfate. Alcohol is added to the acidic salt extract, and resulting precipitate is removed. Solid ammonium sulfate is added to the liquid until saturation and the solution forms two phases with a precipitate of hyaluronic acid at the interface.
  • U.S. Patent No. 4,517,296 to Brace et al. is directed to the preparation of hyaluronic acid in high yield from Streptococcus bacteria under anaerobic conditions in a C0 2 enriched growth medium, separating the bacteria from the resulting broth and isolating hyaluronic acid from the remaining constituents of the broth. Separation of the microorganisms from the hyaluronic acid is facilitated by killing the bacteria with trichloroacetic acid. After removal of the bacteria cells and concentration of the higher molecular weight fermentation products, the hyaluronic acid is isolated and purifies by precipitation, resuspension and reprecipitation.
  • hyaluronic acid One particular fraction of hyaluronic acid (HA) that exhibits excellent matrix formation according to the present invention is hyaluronic sodium having a mean or average molecular weight between 650,000-800,000, preferably 700,000-775,000 with a high decree of purity, 95-105% free, and preferably at least 98% pure, from contamination of related mucopolysaccharides . Furthermore, this hyaluronic acid has a sulphated ash content of less than 15% and a protein content of less than 5%.
  • usable base salts include those safe for animal and human use, such as sodium, potassium, calcium, and magnesium salts or the like.
  • chondroitins are mucopolysaccharides comprising repeating units of D- glucuronic acid and N-acetyl-D-galactosamine . Chondroitin sulphates are important components of cartilage and bone and are excellent for preparing the polymer matrix herein.
  • the negative charged polymers are generally present in the system in amounts which enables a solid gel to be formed.
  • gels are formed using amounts of about 2.0 to about 4.0% by weight with amounts of about 2.1 to about 2.5% by weight being preferred for use as a topical gel .
  • the solutions used to prepare the gel of the present invention may be prepared in a variety of ways.
  • the polymers may be dissolved in water and purified either separately or jointly and then the optional active drug added to the system.
  • a particularly preferred procedure involves separately dissolving the nonionic polymer in water and centrifuging the material to form a solution and then removing impurities. This may be conveniently done at rotation speeds of 2000 rpm for times of about 30 minutes to about two hours.
  • the negative charged polymer may be blended and stirred in water until it is dissolved. This process must be done while avoiding the formation of bubbles and while freeing the polymer of its electrostatic activity. Furthermore, the molecular weight of the polymer must not be significantly changed during processing and as such mild process conditions are required. Processing conditions of 400 - 3000rpm for durations of 16-24 hours have been found acceptable to produce stable solutions or gels of the charged polymer.
  • emulsifiers such as sodium meta- bisulfate
  • antioxidant such as sodium meta- bisulfate
  • preservatives such as benzyl alcohol
  • the drug may be added to the homogenous solution or gel separately once dissolved or disbursed in water. Emulsifiers, suspending agents and preservatives may then be added to this system.
  • One particularly nonlimiting effective material for solubilizing water insoluble drugs is methoxypolyethleneglycol (MPEG) .
  • the formulations may be used topically and also contain conventional pharmaceutical acceptable excipients well known to those skilled in the art, such as surfactants, suspending agents, emulsifiers, osmotic enhancers, extenders and dilutants, pH modifiers as well as fragrances, colors, flavors and other additives.
  • the active drug agents may be blended with the aqueous polymer matrix at the time of manufacture. As such, the drug when in the form of a water- soluble solid is simply diluted with sterilized water or polymer matrix solution and prepared in gel form.
  • the dosage system can be formed with or without the use of pharmaceutically acceptable preservatives.
  • a significant advantage of the dosage form of the present system relates to its ability to allow the drug to slowly diffuse through tissue when administered thus allowing for an effective therapeutic dose to be present for many hours.
  • reference to therapeutically effective doses does not necessarily relate to conventional dosage levels, but does relate to drug levels that achieve an effective therapeutic level at the dose employed, which may be the same level but not at the same frequency of administration previously required for drugs taken orally or by injection. This not only significantly reduces the number of doses required to achieve the same effect, but it also reduces costs, maintenance and health hazards associated with conventional treatment therapies. Additionally, it results in immediate and continued drug release for long periods of time spanning several hours in duration.
  • doses of 1 ml to 75 ml may be administered with preferred doses using 2 to 25 ml of the gelled matrix system.
  • the formulations of this invention may be used to treat a variety of mammal and animal conditions and physical state.
  • One system having a particular application relates to pain management, namely the prevention, treatment and alleviation of pain associated with any disease condition or physical state.
  • the preparations of this invention may treat the following nonlimiting locations or sources of pain below the dermal level of the skin, including, but not limited to knees, ankles, hands, feet and neck.
  • NSAIDs have been known to produce gastric and intestinal irritation.
  • scarring and ulceration of intestinal tract is quite common in patients on short- or long-term NSAID therapy.
  • NSAID therapy for patients suffering from extremely painful, inflammatory conditions which may include osteoarthritis and other inflammatory disorders.
  • new NSAIDs are constantly entering the marketplace, each one, however, with the same potential to cause unpleasant and often serious side- effects .
  • NSAIDs and particularly diclofenac described herein are a much safer way of treating inflammatory disorders including those related to osteoarthritis also known as Degenerative Joint Disease (DJD) .
  • DJD Degenerative Joint Disease
  • diclofenac When a person takes an oral form of diclofenac, typically 100 mg to 150 mg per day, the drug must be circulated through systemic blood and only a small amount ends up in the specific site that is intended for treatment, such as the knee.
  • NSAIDs including, but not limited to, diclofenac, ibuprofen, Aspirin, etc., which as previously mentioned produce an anti-inflammatory effect at the joint level.
  • diclofenac ibuprofen, Aspirin, etc.
  • GI gastrointestinal
  • the transdermal delivery system described herein offers a major alternative especially for those individuals who have a history of undesirable side-effects associated with gastric and intestinal irritation. Also for those patients who have already suffered damage, including ulceration and loss of absorption from the intestinal tract, the transdermal preparations described herein present a new way of providing effective treatment and relief of painful symptoms. It has become common practice of rheumatologists and other specialists treating osteoarthritis and associated disorders to use ulcer-type drugs of the H2 blocking variety including, but not limited to, ranitidine (Zantac) , Pepsid and cimetidine (Tagamet) by Smith Kline.
  • patients treated with the present transdermal diclofenac find that they can function for longer periods of time (4 to 6 hours) and can simply apply more of the therapeutic gel to maintain a continuous reduction in pain and inflammation. In this way, patients who apply the drug topically 3 to 4 times a day can experience sustained around-the-clock relief.
  • transdermal delivery can be substantiated by: 1. Measurable blood levels of diclofenac.
  • Voltaren cream (Ciba-Geigy) is popular for the treatment of osteoarthritic conditions.
  • This preparation contains diclofenac sodium.
  • the manufacturers have not demonstrated to the satisfaction of North American regulators a proven ability of the cream to be transdermally absorbed. Amounts of diclofenac delivered by the cream are considered to be minimal at best.
  • diclofenac as the sodium or potassium salt, is a benzeneacetic acid O 01/39725
  • diclofenac the anion in Voltaren® and Calaflam®, is a nonsteroidal anti-inflammatory drug (NSAID) .
  • NSAID nonsteroidal anti-inflammatory drug
  • diclofenac is not a narcotic.
  • the current invention represents a break-through in that for the first time measurable, detectable levels of diclofenac can be delivered to affected sites. For those patients who experience mild intestinal discomfort following administration, it is recommended that the transdermal gel preparation described herein, be administered after meals.
  • the transdermal polymer matrix must contain a non-ionic polymer which facilitates in retarding the absorption of the active drug through the skin and delays or slows down the natural absorption of the negatively charged polymer in an animal.
  • the active drug would not be delivered transdermally into the site targeted for treatment at levels which are therapeutically effective.
  • these materials are necessary to provide thorough penetration of skin layers including the O 01/39725
  • TEST PROCEDURE I Patient LHN' s complaint is of headache and pain in the back of the neck.
  • This 52-year-old lady has a long history of occasional headaches and occasional neck pain.
  • the patient has a history of 7 motor vehicle accidents. She underwent facet rhizolysis about three years ago. This almost entirely relieved her headaches.
  • the diclofenac gel has successfully relieved her neck ache on three different occasions. Each time the pain relief was almost 100%. In addition, it stopped the beginnings of a headache on each occasion.
  • the preparations of this invention may be used to treat a wide variety of dermatologic disorders.
  • exemplary, non-limiting disorders include dermatitis conditions such as: Contact Dermatitis: O 01/39725
  • Pressure sores Factors that precipitate pressure sores include loss of pain and pressure sensations (which ordinarily prompt the patient to shift position and relieve the pressure) and the thinness of fat and muscle padding between bony weight- bearing prominences and the skin. Disuse atrophy, malnutrition, anemia, and infection play contributory rate. Spasticity, especially in patients with spinal cord injuries, can place a shearing force on the blood vessels to further compromise circulation.
  • pressure The most important of the extrinsic factors is pressure. Its force and duration directly determines the extent of the ulcer. Pressure severe enough to impair local circulation can occur within hours in an immobilized O 01/39725 patient, causing local tissue anoxia that progresses, if unrelieved, to necrosis of the skin and subcutaneous tissues. The pressure is due to infrequent shifting of the patient's position; friction and irrigation from ill- adjusted supports or wrinkled bedding or clothing may be contributory. Moisture, which may result from perspiration or from urinary or fecal incontinence, leads to tissue maceration and predisposes to pressure sores.
  • stage 1 consists of skin redness that blanches or disappears on pressure; the skin and underlying tissues are still soft.
  • Stage 2 shows redness, edema, and induration, at times with epidermal blistering or desquamation.
  • stage 3 the skin becomes necrotic with exposure of fat and drainage from wound.
  • stage 4 necrosis extends through the skin and fat to muscle; further fat and muscle necrosis characterizes stage 5.
  • stage 6 bone destruction begins, with periostitis and osteitis, progressing finally to ostemyelitis, with the possibility of septic arthritis, pathologic fraction and septicemia .
  • the major problem in treating decubitus ulcer is that the ulcer is like an iceberg, a small visible surface with an extensive unknown base, and to date there is no good method to determine the extent of tissue damage. Ulcers that have not advanced beyond stage 3 may heal spontaneously if the pressure is removed and the area is small . Stage 4 ulcers require debridement; some may also require deeper surgery. When the ulcers are filled with pus and necrotic debris, application of dextranomer beads or other and newer hydrophilic polymers may hasten debridement without surgery. Conservative debridement of necrotic tissue with forceps and scissors should be instituted. Some debridement may be done by cleansing the wound with 1.5% hydrogen peroxide. Wet dressings of water
  • Affected bone tissue requires surgical removal; disarticulation of a joint may be needed.
  • a sliding full-thickness skin flap graft is the closure of choice, especially over large bony prominences (e.g., the trochanters, ischia, and sacrum), since scar tissue cannot develop the tolerance to pressure that is needed.
  • Peripheral vascular distress due to diabetes is also treatable.
  • the primary cause of ulceration in diabetic patients is the occlusion of the blood supply to the extremities, as well as sensory denervation. Both factors contribute to the impaired ability of the patient to perceive trauma which has occurred, thus possibly causing a compounding of the damage due to lack of timely treatment.
  • reduced blood supply combined with decreased cellular immunity greatly increase the risk of fungal and bacterial infections .
  • peripheral vascular distress due to diabetes is complex, because management of the underlying condition is primary. Further, stabilization of the diabetic condition alone will not necessarily alleviate the ulcerations. If possible, patients are advised to avoid weight bearing activities and appropriate orthotic protection applied. Production and application of a cushioned layer of the matrix incorporating the appropriate antiviral and/or antibiotic agent is an effective as well as efficient treatment.
  • Motion sickness is caused by excessive stimulation of the vestibular apparatus during motion. While the complete physiological mechanism is not fully understood, it is believed that a combination of visual stimuli, poor ventilation and emotional factors precipitate attacks of motion sickness.
  • a variety of treatment options may be employed. Drugs such as dimenhydrate, diphenhydramine, meclinzine, cyclizine, promethazine, diazepam and scopolamine, as well as phenobarbital, in the case of psychological distress, may be employed. Utilization of a dermal patch produced with an effective motion sickness medicament applied approximately one to four hours prior to exposure to precipitating factors can deliver an effective and prolonged dosage. If extended exposure to travel is anticipated, a dermal patch produced with a more appropriate dosage amount may be administered.
  • the present formulations are able to extend relief or treatment from normally several hours to at least several days of relief.
  • the use of repeat applications enhances drug release which significantly reduces drug dependence. It also results in the relief of continued tissue damage and may even assist in tissue repair.
  • the formulations of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known in the pharmaceutical art.
  • an effective but nontoxic amount of the system is employed in treatment.
  • the dose regimen for administering drugs or treating various conditions, such as pain as described above is selected in accordance with a variety of factors including the type, age, weight, sex, and medical condition of the subject, the severity of the pain, the route of administration and the particular complex or combination of drugs employed. Determination of the proper dose for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum doses of the compound. Thereafter, the dose is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • amounts of matrix with or without drug may vary from 0.0001% to about 75% by weight of the system when using topically with 2 to 25 ml concentrations and preferably in 3 to 10 ml amounts.
  • the formulations of this invention are particularly useful in the administration of drugs that could be previously administered only orally.
  • nonionic polymers are cellulose derivatives and particularly those selected from the group O 01/39725
  • a particularly preferred HEC concentration is about 0.2% to about 1.0% by weight of the matrix.
  • medicaments which may be administered topically may be used in the delivery system according to this invention. These include drugs from all major categories, and without limitation, for example, anesthetics including benzocaine, tetracaine, mepivacaine, prilocaine, etidocaine, bupivacaine and lidocaine; analgesics, such as acetaminophen, ibuprofen, fluriprofen, ketoprofen, voltaren (U.S. Patent No.
  • nonsteroidal anti- inflammatories selected from the group consisting of naproxen, acetaminophen, ibuprofen, flurbiprofen, ketoprofen, phenacetin, salicylamide, and indomethacin
  • antibiotics including amebicides, broad and medium spectrum antibiotics, fungal medications, and anti-viral agents and specifically including erythromycin, penicillin and cephalosporins and their derivatives
  • central nervous system drugs such as thioridazine, diazepam, meclizine, ergoloid mesylates, chlorpromazine, carbidopa and levodopa
  • metal salts such as a potassium chloride and lithium carbonate
  • minerals selected from the group consisting of iron, chromium, molybdenum and potassium
  • immunomodulators immunosuppressives
  • thyroid preparations such as synthetic thyroid hormone, and thyroxine sodium
  • steroids such as synthetic thyroid hormone, and thyroxine sodium
  • Chemotherapeutics such as Actinomycin D, adriamycin, altretamine, asparaginase, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxol, taxotere, tamozolomide, thioguanine, thiotepa, tomud
  • chemotherapeutics useful in combination and within the scope of the present invention are buserelin, chlorotranisene, chromic phosphate, dexamethasone, estradiol, estradiol valerate, estrogens conjugated and esterified, estrone, ethinyl estradiol, floxuridine, goserelin, and prednisone.
  • compositions of this invention include their uses as 1) a medical device, 2) for drug delivery, 3) the application of a diagnostic agent or 4) the prevention of post operative adhesions.
  • One useful aspect of the present invention is that of concentrating the matrix to various degrees depending upon intended usage.
  • the step of concentrating must be practiced under conditions that avoid degradation of the hyaluronic acid and its salts. These conditions can be determined without undue experimentation by a person of ordinary skill in the art. Concentrating is generally practiced until between about 10 percent by weight and about 70 percent by weight, and preferably until between about 20 percent by weight and about 50 percent by weight, of the water is removed from the first aqueous solution.
  • the water removal step is affected by controlling of the temperature of the solution. Widely varying temperatures can be employed for the concentrating step, however, the temperature is generally maintained from about 10°C to about 80°C and preferably from about 30°C to about 60°C. subatmospheric pressure may also be used. While, superatmospheric pressure is suitable, this step is preferably practiced at atmospheric pressure, namely about 760 mmHg.
  • the concentrated solutions of the present invention may be prepared by slowly adding hyaluronic acid to sterilized water being stirred at approximately 200-600 rpms .
  • the molecular weight and purity of the hyaluronic acid as described previously are of the utmost importance and must not be significantly changed during processing, therefore mild processing conditions are required.
  • Stirring is continued until the HA has completely dissolved into the water and a crystal clear viscous solution has formed.
  • a quantity of the solution is removed and placed in a clean vessel, where constant stirring is continued.
  • the vessel is then placed in a warm environment and is monitored.
  • the water content is removed by evaporation without causing the molecular degradation of the HA.
  • the amount of water removal may be determined by the weight reduction of the solution. If weighing the solution does not indicate the desired amount of water either present or removed, the vessel may be returned to the warm environment for further water removal.
  • the composition further comprises an active therapeutic agent.
  • active therapeutic agent which is compatible with hyaluronic acid and its salts can be employed in the present invention.
  • a wide variety of medicaments which are administered may be used in the delivery system according to this invention.
  • NAHA sodium hyaluronate
  • NAHA is a major carbohydrate component of the extracellular matrix and can be found in skin, joints, eyes and most other organs and tissues. It has a linear co-polymer structure that it is completely conserved throughout a large span of the evolutionary tree, indicating a fundamental biological importance. Amongst extracellular matrix molecules, it has unique hydroscopic, rheological and viscoelastic properties. Sodium hyaluronate binds to many other extracellular matrix molecules through its complex interaction with matrix components and cells.
  • sodium hyaluronate has an important biological role in skin wound healing, by virtue of the fact that during wound healing levels of sodium hyaluronate are elevated temporarily in granulation tissue. It has been determined that there is a specific binding interaction between fibrin, the major clot protein, and sodium hyaluronate which is a constituent of the wound extracellular matrix. The binding interaction may provide the driving force to organize a three-dimensional NAHA matrix which attaches to the fibrin matrix.
  • hyaluronate acid derived matrix which is unique to the polymer matrix, is to facilitate wound healing and to prevent complications such as those found when scarring and adhesions are formed.
  • the prime purpose of providing an impregnated web or padded web with a stable, transdermal sodium hyaluronate matrix in the form of the polymer matrix complex is important in regulating the molecules which control cellular function and which are involved in the inflammatory response and new blood vessel formulation amongst other factors which are involved in wound healing.
  • Matrices of the present invention alone or incorporating a drug, have been found to be effective in the treatment and healing of wounds. Therefore, the matrices of the present invention may be utilized without incorporating an additional drug.
  • the same rationale can be applied to wounds of a long-standing nature where the natural biological components including the extracellular matrix have been compromised as in slow healing diabetic ulcers and bed sores.
  • the thrust of the current experimental work is to examine the compatibility of the components used for the construction of the bandage material, such as bandage products manufactured by those well known in the art and conventionally available, with those of typical matrices used for various products.
  • a matrix was formulated to serve as a prototype polymer matrix which would be suitable for the prevention of adhesions and scarring when impregnated or otherwise combined with the Web bandage.
  • Various matrices including Diclofenac Matrix and Eczema Matrix, produced by the process of Example 1, were placed directly on the surface of the web.
  • Various methods were used to dry the matrix including direct heat, infra- red heat and room temperature (3-5 minutes).
  • the Web with matrix film was subjected to a variety of experiments. These included boiling, heating and otherwise using extreme adverse conditions to produce deterioration and destruction of the Web/Matrix combination material. The results of these experiments show that heat did not adversely affect the inherent qualities of the Web/Matrix; that is, by heating with forced heat through a blower or with ultra-violet heat. The adhesive properties of the web are not reduced or otherwise compromised by the addition of polymer matrix.
  • the polymer matrices when applied directly to the padded portion of the Web/bandaid material absorb totally either when dried by the methods described above or when left for approximately 3-5 minutes on the surface of the padded portion at room temperature.
  • a pro-forma wound healing matrix was manufactured using the process of Example 1.
  • the formula was a follows:
  • NAHA sodium Hyaluronate
  • HEC low weight Hydroxyethylcellulose
  • Methoxyhydroxypolyethylene glycol 10% Sodium D-Pantothenate 1.5% Water q.s.
  • the pro-forma wound healing matrix produced a film when heat was applied to the bandaid-type pad (Large Water Block Plus) which has a padded area of 2.5 x 5 cm.
  • the heat method used was forced air drying or UV light.
  • the matrix was applied to the pad alone and left for 3-5 minutes at room temperature, it dried and was integrated into the pad without producing a film.
  • This method has several advantages: the integrated padded portion does not need moisture for rehydration, the material is active immediately when placed on the skin, and the cover for the bandaid keeps the skin dry.
  • Niacin Matrix 0.5 ml of Niacin Matrix was applied to the patch portion of the bandaid and was placed on the left arm of a subject and left in place for half-an-hour . The result was that reddening of the skin on the patch area was evident after the bandaid was removed.
  • Niacin Matrix 0.75 ml of Niacin Matrix was applied, using similar techniques to the patch. The patch was placed on the subject's right arm and was left in place for half-an-hour. There was increased reddening of the skin which radiated about 1 inch outward.
  • the objective would be to impregnate or coat the covering to be applied to the skin with an appropriate amount of matrix.
  • the material covering the patch following matrix impregnation may be of the Teflon coated variety to avoid interaction or contact, or be made of any other suitably approved polymer material generally used for medical applications. Such materials should remain inert or non-reactive with the matrix material .
  • the design and shape of the wound healing product will depend on the nature of the wound to be dressed. Obviously the length is determined again by the length of the wound itself. When treating ulcerated wounds which occur through illness or a deficiency, as in the case of bed sores, circular designs may work well.
  • Another factor that would appear to be favorable is the ability of the health care professional treating the patient or the patient themselves, to use additional matrix, where necessary, to heal stubborn conditions such as diabetic or slow healing ulcers. This would appear to be able to be accomplished simply by adding additional matrix to the already impregnated product at the time of application.
  • the Matrix can also be presented in individual dispensing cartridges containing an appropriate amount of product. Such single dose cartridges are available through several sources. One possible source is Confab in Quebec, even though other sources well known in the art can be used. The use of these cartridges may be customized for polymer matrix formulations and could be used to provide additional matrix for application to Web/pad materials in the treatment of difficult cases.
  • Into a sterilized glass vessel is added 500 ml of the sterile water which is stirred at 400-600 rpms . Slowly add 13.7 grams of HA having an average molecular weight of around 700,000 to 775,000.
  • a quantity (500 grams) of the above viscous solution is placed in a clean beaker of known weight.
  • a magnetic stirrer of known weight is placed in the beaker.
  • the beaker containing the viscous solution and the stirrer is placed in a laboratory hood where the beaker and its contents are maintained in a warm location at 40°C while being constantly stirred. Under these conditions water is removed from the viscous solution without any molecular degradation of the HA.
  • the beaker is weighed. If the weight reduction does not indicate removal of the desired amount of water, the beaker, with its contents, is returned to the warm location in the hood for further water removal.
  • HEC Hydroxyethylcellulose
  • HA Hyaluronate Sodium
  • Into a sterilized glass vessel is added 500 ml of the sterile water which is stirred at 400-600 rpms. Slowly add 13.7 grams of HA having an average molecular weight of around 700,000 to 775,000 and a purity described previously. Allow to stir for 10 to 20 hours until all the HA has dissolved into the water and a crystal clear viscous solution has formed.
  • a quantity (500 grams) of the above viscous solution is placed in a clean beaker of known weight.
  • a magnetic stirrer of known weight is placed in the beaker.
  • the beaker containing the viscous solution and the stirrer is placed in a laboratory hood where the beaker and its contents are maintained in a warm location at 40°C while being constantly stirred. Under these conditions water is removed from the viscous solution without any molecular degradation of the HA.
  • the beaker is weighed. If the weight reduction does not indicate removal of the desired amount of water, the beaker, with its contents, is returned to the warm location in the hood for further water removal.
  • This example demonstrates the formation of a transdermal nonsteroidal anti-inflammatory preparation known as diclofenac which produces relief of osteoarthritic and associated pain in areas affected by the disease.
  • areas include, but are not limited to, knees, ankles, feet, back, neck, elbows, and hips.
  • the present example also demonstrates the formation of a transdermal preparation containing the NSAID drug which when administered topically to sites affected by rheumatic or osteoarthritic disease will have an analgesic and beneficial effect.
  • the onset of this beneficial effect in the form of pain relief and reduction of inflammation occurs between 10 and 20 minutes following topical administration and lasts for up to 6 hours.
  • the dosage range for the drug is between 2-4 ml (60 mg-120 mg) depending on the severity and site of the affected area.
  • Into a sterilized glass vessel is added 1062.5 ml of sterile water which is stirred at 1500 to 2000 rpm. Slowly add 34.5 grams of HA, having an average molecular weight of around 700,000 to 775,000 and a purity described above. Allow to stir for 16 to 20 hours until all of the HA polymer has dissolved into the water and a crystal-clear viscous solution has formed.
  • the final mixture is clear with a slight green tint following 15 to 20 hours of further mixing at 2000 rpm.
  • the final product should be transferred, using aseptic techniques, to 25 ml borasylicate glass jars with a lined cap.
  • Example 4 The formula and method of manufacture of Example 3 are repeated for diclofenac potassium. The only difference is that MPEG is not used.
  • HEC Hydroxyethyl cellulose
  • Into a sterilized glass vessel is added 1062.5 ml of sterile water which is stirred at 1500 to 2000 rpm. Slowly add 34.5 grams of HA, having an average molecular weight of around 700,000 to 775,000 and a purity described previously. Allow to stir for 16 to 20 hours until all of the HA polymer has dissolved into the water and a crystal- clear viscous solution has formed.
  • the rpm speed for the purpose of addition of diclofenac should be increased to 2500, and the entire 45 grams of diclofenac should be completed within 15 minutes.
  • the final mixture is clear with a slight green tint following 15 to 20 hours of further mixing at 2000 rpm.
  • the final product should be transferred, using aseptic techniques, to 25 ml borasylicate glass jars with a lined cap.
  • Example 3 The general manufacturing procedure of Example 3 is repeated for a topical dermalogical preparation.
  • the main difference in composition is the use of methylparabin as a preservative .
  • HA hyaluronate
  • HEC Hydroxyethyl cellulose
  • Example 1 Prior to dissolving the HA into the water, methyl parabin is dissolved and then HA added thereto. The remaining process steps of Example 1 were then repeated.
  • Example 6 The following describes experiments with respect to a pro-forma wound healing dressing. The formula was as follows :
  • NAHA Sodium Hyaluronate
  • HEC Hydroxyelthylcellulose
  • MPEG Mthooxyhydroxypolyethylene glycol
  • the pro-forma wound healing matrix produced a sheet or film when heat was applied to the mixture.
  • the heat method used was force air drying or ultraviolet light.
  • the wound healing matrix was poured into a petri dish to the depth of 0.2 inches and left for 30 minutes at room temperature the same sheet was produced. This method has several advantages: the sheet does not require rehydration for treatment purposes, the sheet is immediately active when placed on the skin and the sheet is easily protectable by a gauze or the type of dressing fixative material.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials Engineering (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions semi-solides de médicaments à libération lente basées sur l'acide hyaluronique et es sels, et concerne plus particulièrement la fabrication et l'utilisation de telles compositions.
EP00992485A 1999-11-08 2000-11-08 Preparations de medicaments Withdrawn EP1231897A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US16414999P 1999-11-08 1999-11-08
US164149P 1999-11-08
PCT/US2000/041961 WO2001039725A2 (fr) 1999-11-08 2000-11-08 Preparations de medicaments

Publications (1)

Publication Number Publication Date
EP1231897A2 true EP1231897A2 (fr) 2002-08-21

Family

ID=22593194

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00992485A Withdrawn EP1231897A2 (fr) 1999-11-08 2000-11-08 Preparations de medicaments

Country Status (4)

Country Link
EP (1) EP1231897A2 (fr)
AU (1) AU4504201A (fr)
CA (1) CA2390841A1 (fr)
WO (1) WO2001039725A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2005079824A1 (ja) * 2004-02-25 2008-01-10 英元 日下 竹エキスを主成分とした飲料及び医薬
US7972636B2 (en) 2004-02-25 2011-07-05 Hidemoto Kusaka Beverage and medicament containing bamboo extract as a main ingredient
EP2252262B1 (fr) 2008-01-18 2020-03-18 Dow Global Technologies LLC Procédé pour améliorer la solubilité aqueuse d'actifs médiocrement solubles à l'aide de méthoxy-polyéthylène glycol

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059123A (en) * 1990-05-14 1991-10-22 Jernberg Gary R Periodontal barrier and method for aiding periodontal tissue regeneration
US5783214A (en) * 1994-06-13 1998-07-21 Buford Biomedical, Inc. Bio-erodible matrix for the controlled release of medicinals

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0139725A3 *

Also Published As

Publication number Publication date
AU4504201A (en) 2001-06-12
CA2390841A1 (fr) 2001-06-07
WO2001039725A2 (fr) 2001-06-07
WO2001039725A3 (fr) 2002-05-10

Similar Documents

Publication Publication Date Title
AU748516B2 (en) Topical drug preparations
US6387407B1 (en) Topical drug preparations
US5529987A (en) Hyaluronic acid-urea pharmaceutical compositions and uses
CZ290637B6 (cs) Kombinační topické prostředky pro léčení bolesti
US20020172712A1 (en) Antiemetic, anti-motion sustained release drug delivery system
JPH0739347B2 (ja) 硫酸化糖類の用途
CZ9300229A3 (cs) Kombinační prostředky pro léčení bazocelulárního karcinomu nebo aktinických keratóz
ES2222581T3 (es) Preparaciones de medicinas para tratar disfuncion sexual.
US5550112A (en) Hyaluronic acid-urea pharmaceutical compositions and uses
KR20180059748A (ko) 고농도 생물 발효 히알루론산 나트륨으로 구성된 국소성 중합체 기지 합성물 및 그 사용
WO2004100923A1 (fr) Composition a usage externe administree par voie percutanee
JPH0776175B2 (ja) 損傷されたかまたは病気になった組織の局所的処置用の組成物および方法
CN105013001B (zh) 一种妇科医用生物水凝胶功能敷料及其制备方法
US20020037319A1 (en) Drug preparations
EP1231897A2 (fr) Preparations de medicaments
WO2023187632A1 (fr) Composition, application de la composition, bio-masque d'hydrogel de préparation cosmétique sous la forme d'une compresse, procédé de fabrication de la préparation
JP2004523521A (ja) 非代謝性の糖質と高分子吸収剤とを用いた細胞再生及び／又は細胞分化の促進
WO2011123619A2 (fr) Mélanges perméables, procédés et compositions pour la peau
CN120381433B (zh) 一种促进烧烫伤及其他创面愈合的抗感染药膏及其制备方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020607

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL PAYMENT 20020607;LT PAYMENT 20020607;LV PAYMENT 20020607;MK PAYMENT 20020607;RO PAYMENT 20020607;SI PAYMENT 20020607

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040602