WO1998022097A2 - Composition d'une matrice a liberation controlee utilisant un melange d'acide poly(acrylique) et d'un polymere ou d'un monomere polaire - Google Patents

Composition d'une matrice a liberation controlee utilisant un melange d'acide poly(acrylique) et d'un polymere ou d'un monomere polaire Download PDF

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WO1998022097A2
WO1998022097A2 PCT/US1997/021280 US9721280W WO9822097A2 WO 1998022097 A2 WO1998022097 A2 WO 1998022097A2 US 9721280 W US9721280 W US 9721280W WO 9822097 A2 WO9822097 A2 WO 9822097A2
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poly
acrylic acid
composition according
carbopol
monomer
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PCT/US1997/021280
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WO1998022097A3 (fr
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Jane Pei-Fan Bai
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Bio Advances, Llc
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Priority to AU72981/98A priority Critical patent/AU7298198A/en
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Publication of WO1998022097A3 publication Critical patent/WO1998022097A3/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • This invention relates to mucoadhesive polymer blend compositions of poly(acrylic acid) and a polar polymer or monomer, wherein the polar polymer or monomer has a ratio of carbon atoms to oxygen atoms and of carbon atoms to hydroxyl groups equal to or less than 1.9: 1 and 5: 1 , respectively, to control the release of soluble bioactive agents, including small molecule drugs, peptides, proteins, and antigens, to the mucosal tissues.
  • soluble bioactive agents including small molecule drugs, peptides, proteins, and antigens
  • Preferred embodiments include compositions of carboxymethyl cellulose/poly(acrylic acid), hydroxyethyl cellulose/poly(acrylic acid), propylene glycol alginate/poly(acrylic acid), dextran/poly(acrylic acid), hydroxypropyl cellulose/poly (aery lie acid), alginic acid/poly(acrylic acid), D-mannitol/poly (acrylic acid), and xylitol/poly (acrylic acid).
  • Hydrogen bonding between polymers facilitates the miscibility of two polymers which have different solubilities in water or polar solvents, and the resulting matrix is transparent and swellable in water.
  • Polymer blends have been designed to control the release of the biologically active agent. The application of these polymer blends to the controlled release of therapeutic agents will be extremely useful if the production method is easy and cost-effective.
  • poly (acrylic acid)-based polymers with a wide range of molecular weight are particularly useful for the controlled release adjacent to the absorptive mucosal surface, since these polymers are mucoadhesive.
  • poly (acrylic acid)-based polymers with a wide range of molecular weight are particularly useful for the controlled release adjacent to the absorptive mucosal surface, since these polymers are mucoadhesive.
  • Cascone et al. Biomaterials (1995), 16:569-574 have disclosed the use of hyaluronic/poly(acrylic acid) sponges formed by thermal treatment at 130°C and with protein added after the formation of the sponge.
  • the poly(acrylic acid) utilized has a molecular weight of 250,000 and thermal treatment at a very high temperature, 130°C. is necessary to induce the cross-linking.
  • Carbopol ® and hydroxypropylcellulose were used to form a buoyant hydrogel matrix with citric acid and sodium bicarbonate by Kim et al. , Ackee Hakhoechi, 26: 137-144, 1996. Citric acid and sodium bicarbonate were used to produce CO 2 gas in aqueous solution, thereby inducing buoyancy.
  • This report describes a system with a property which is completely opposite to what is desired for a mucoadhesive matrix. Mucoadhesive polymer blends are for adherence to the mucosal tissue instead of floating in gastric or intestinal fluid.
  • microspheres containing poly (acrylic acid) crosslinked with ⁇ -cyclodextrin or maltose using olive oil, a heating temperature of 105-115°C, and centrifugation has been described by Bibby et al , Proc. Int. Symp. Controlled Release Bioact. Matr. 24: 545-546, 1997.
  • the maltose has the low number ratio of carbon atoms to oxygen atoms and that of carbon atoms to hydroxyl groups, the process involves an oil and tedious centrifugation procedures for encapsulation.
  • the amount of drugs encapsulated in the microspheres can not be predetermined. It is inconvenient and inefficient for a large scale production.
  • the poly (acrylic acid) used is Carbopol ® 907, which is not pharmaceutical grade.
  • Dapper et al in U.S. Patent 5,487,895, disclose a controlled release system of microspheres of collagen/poly(acrylic acid) where the crosslinking reaction involves collagen, cross-linking agent and acetic acid with the aid of the organic solvents, toluene and acetone. Toluene has high toxicity and is, therefore, not suitable for preparation of medications to be used by humans.
  • Acharya U.S. Patent 5, 110,605
  • Controlled release of peptides/proteins is specially useful for increasing and prolonging contact with the mucosal tissues, since absorption of these molecules is low.
  • Gombotz et al in U.S. Patent 5,451,411 , describe a controlled release oral delivery method involving crosslinking of alginate bead with multivalent cation, such as calcium.
  • Poly (aery lie acid) having a molecular weight of 75 to 100 kDa is incorporated in the system to shield the cationic therapeutic agents from interaction with alginate. Dropping of the solution of alginate and poly (acrylic acid) into the calcium solution is necessary to for the beads.
  • the technology is not adaptable for forming a layer on a granule or tablet or suppository or insert or patch.
  • None of these inventions or reports provide an easy method to produce a controlled release mucoadhesive, swellable gel film involving poly (aery lie acid), which can flexibly form a firm gel layer on any support, such as a tablet, granule, suppository, particle, transdermal patch, or insert, and which is adaptable to any shape or contour.
  • Poly(acrylic acid) based polymers including poly(acrylic acid) crosslinked with allyl pentaerythritol, such as Carbopol ® 97 IP, are not water-soluble, but swellable once hydrated.
  • Carbopol polymers are produced by BF Goodrich Specialty Chemicals.
  • U.S. Patent 2,798,053 discusses how Carbopol polymers are produced.
  • the Product Bulletins 16 and 17 for Carbopol published by BF Goodrich Specialty Chemicals (December 1994), particularly describe the use of such polymers in pharmaceutical applications, especially for the preparation of bioadhesive compositions for use in mucosal environment.
  • the Bulletin describes a wide variety of drugs and excipients which can be utilized in combination with the poly (acrylic acid) product, but most surprisingly, indicates that "highly water soluble excipients like sugar should be avoided, as these excipient create osmotic forces that may break up the Carbopol ® gel layer. "
  • the mucosal surface includes gastrointestinal, nasal, buccal and intra-tracheal mucosae. These mucosal tissues are the major sites for absorption of small molecules and large bioactive macromolecules, and for uptake of antigen to induce immunological responses. Controlled release at the mucosal surface needs to consider the resident time at the site of absorption. A release over several days is not considered optimal or beneficial considering since there typically is less than a 24 hour residence time in mucosal tissues, due to the efficient clearance by mucociliary system of nasal and intra-tracheal mucosal tissues and due to gastrointestinal mobility.
  • a soluble antigen induces systemic tolerance to the antigen, which is different from immunity induced by antigen taken up in the form of microparticulates, such as antigen formulated in nanoparticles and microparticles.
  • Such administration has been used to delay /prevent the onset of autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), experimental autoimmune uveitis (EAU) and encephalomyelitis (EAE)(a disease model induced for the study of multiple sclerosis), adjuvant- and collagen-induced arthritis (Weiner et al , Annu. Rev. Immunol (1994) 12:809-37, 1994).
  • IDDM insulin-dependent diabetes mellitus
  • EAU experimental autoimmune uveitis
  • EAE encephalomyelitis
  • the antigens tested include insulin for IDDM, myelin basic protein and its fragments for EAE, S-antigen for EAU, and collagen and its fragments for arthritis. Though less studied, administration to other mucosal tissues, nasal, tonsil and respiratory, has also been shown to be effective in inducing immunological tolerance to antigen (Weiner et al , Annu. Rev. Immunol (1994) 12:809-37; Staines et al , Clin. Exp. Immunol. (1996) 103:368-375). Intestinal, nasal, tonsil, respiratory mucosal immunological tissues underlying the mucosal layer constitute the common mucosal immune system. The mucosal immune system consists of lymphoid nodules, Peyer's patches, lamina limbal (M cells) specializing in antigen uptake, and others depending the anatomical locations.
  • M cells membraneous cells
  • antigens In order to induce immunological tolerance, antigens have to be taken up in soluble form, and microspherical controlled release systems taken up by mucosal tissues are not desirable. Controlled release of soluble antigen from poly (acrylic acid)-based polymer blends will prolong interaction with the mucosal lymphoid tissues. They are suitable for maximizing the in vivo contact of the antigen with mucosal immune tissues and to increase the number of mucosal lymphoid cells exposed to the antigen. While many drug delivery formulations presently exist, none of these utilize the mild conditions which are necessary for the efficient administration of sensitive bioactive proteins, peptides, and antigens to the mucosal tissues at the desired rate of delivery. Therefore, a need exists for a suitable mucoadhesive composition which can incorporate into its matrix a bioactive agent during the process of matrix formation.
  • Controlled release of small molecule drugs at the mucosal tissues in the oral cavity, intestine, stomach, rectum and vagina can often provide convenience to the patient and minimize the fluctuation of drug levels in blood with minimal dosing frequency.
  • FIGURE 1A is a graph showing the release profile of insulin-FITC from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose.
  • FIGURE IB is a graph showing the release profile of insulin-FITC from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose.
  • FIGURE 2 is a graphical presentation of the release profile of diltiazem, a cardiovascular drug, from the polymer blend matrix of Carbopol 971 P NF and hydroxyethylcellulose .
  • FIGURE 3 is a graphical presentation of the release profile of triamterene, a diuretic, from the polymer blend matrix of Carbopol 97 IP NF and hydroxyethylcellulose .
  • the present invention relates generally to a novel poly(acrylic acid) blend useful for drug delivery to the mucosal tissues. More particularly, this invention relates to a mucoadhesive controlled-release matrix composition which comprises a bioactive agent incorporated in the matrix comprising a poly(acrylic acid) and a water-soluble polymer or monomer, with the carbon-oxygen ratio of the polymer or monomer being less than or equal to 1.9: 1 and the carbon-hydroxyl group ratio of the polymer or monomer being less than or equal to 5: 1 , the weight ratio or the poly (acrylic acid) to water-soluble polymer or monomer ranging from 1 :90 to 90: 1 , and preferably from 20:80 to 80:20, said composition being prepared at a temperature of less than about 120°C.
  • the invention comprises a mucoadhesive controlled-release matrix composition wherein the bioactive agent is a small molecule drugs or protein/peptide, or antigen, in an amount of about 0.01-80%, and preferably, about 1-40%, by weight of the composition.
  • the bioactive agent is a small molecule drugs or protein/peptide, or antigen, in an amount of about 0.01-80%, and preferably, about 1-40%, by weight of the composition.
  • the present invention also extends to the process for preparing a mucoadhesive composition under mild conditions, and to therapeutic methods of using the so-prepared compositions.
  • the poly (aery lie acid) utilized in the present invention can be any of the commercially available poly (acrylic acid) polymers.
  • the poly (aery lie acid) can be loosely crosslinked or have no cross-linking.
  • Poly (acrylic acid) polymers with crosslinking or with no crosslinking are commercially available from a number of sources.
  • Highly preferred poly (acrylic acid) polymers are those crosslinked with less than 10% allyl pentaerythritol, which are available from BFGoodrich specialty Chemicals, Cleveland, Ohio, under the tradename of Carbopol ® .
  • Carbopol ® 971P Especially preferred are the pharmaceutical grade Carbopol ® 971P, Carbopol ® 934P and Carbopol ® 974P poly(acrylic acid) polymers.
  • These polymers are crosslinked, and swell up to 1000 times their original volume (and ten times their original diameter) in water to form a gel when exposed a pH environment above 4-6. Above their pKa of 6 . +0.5, the carboxylate groups on the polymer backbone ionize, resulting in repulsion between the anions and further increasing the swelling of the polymer.
  • These crosslinked polymers do not dissolve in water, but instead form colloidal gel dispersions.
  • polymers can absorb water of more than 15% their dry weight when swelling (Bulletin 17, December, 1994, BF Goodrich Specialty Chemicals). According to available product literature, these polymers possess an approximate molecular weight of 3.5 million, due to their cross-linked nature.
  • Poly(acrylic acid), poly(acrylic acid) crosslinked with about 10% or less allyl pentaerythritol, Carbopol 97 IP, Carbopol 974P, sodium carboxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose are bioadhesive polymers. These polymers can thus provide a prolonged close contact with mucosal surface to increase absorption through mucosal tissues and interaction with mucosal immune systems.
  • the preferred polymers should have a low number ratio of carbon atom to oxygen atom, that of carbon atom to nitrogen atom, and that of carbon atom to hydroxyl group. This principle can extend to the blend of monomer with similar characteristics and poly (acrylic acid).
  • the Carbopol" polymers are usually mixed with bioactive agents, and other pharmaceutical excipients, such as diluents, disintegrants and coloring agents, and the resulting mixture is directly compressed into tablet.
  • bioactive agents such as diluents, disintegrants and coloring agents
  • other pharmaceutical excipients such as diluents, disintegrants and coloring agents
  • the matrix microparticles are often partially hydrated with the inner core unhydrated because of water penetration into the core being deterred by the strong hydrogen bonding network with water in the outer hydrated layer.
  • the Carbopol polymers are preferred for use in the matrix compositions of the present invention to provide a versatile method for the control of the release of the bioactive agent.
  • the Carbopol ® /polar polymer matrix containing the bioactive agent can be compressed into tablets, optionally containing other excipients and active agents.
  • the Carbopol ® /polar polymer mixture containing the bioactive agent can be spray-dried onto sugar/starch seeds to form particles and granules or spray-dried onto inserts or suppositories, or sprayed to form a controlled release layer on the transdermal or buccal patches.
  • the Carbopol ® /polar polymer mixture can be coated on to the surface of any object to form a controlled release layer for any non-parenteral administration.
  • the polar polymers and monomers utilizable in the present invention are those which contain numerous carboxyl and hydroxyl groups so as to form blends with poly (aery lie acid) and have a carbon-oxygen ratio of less than or equal to 1.9: 1 , and the carbon-hydroxyl group ratio of the polymer or monomer being less than or equal to 5: 1.
  • Examples of such polar polymers include, but are not limited to, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, propylene glycol alginate, hydroxy ethyl cellulose, dextran, hydroxypropyl cellulose, alginic acid, and sodium alginate.
  • Examples of such polar monomers with capability to form extensive hydrogen bonding can also be mixed with the swellable polymers.
  • Those of pharmaceutical grade are especially desirable, including, but not limited to, those such as D-mannitol and xylitol.
  • Preferred for use in the practice of this invention are the polar polymers and monomers, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, dextran, alginate, propylene glycol alginate, xylitol and D-mannitol. Hydroxyethyl cellulose and hydroxypropyl cellulose of various molecular weights and viscosity are also within the scope of the present invention.
  • the bioactive agent utilized in the mucoadhesive compositions of the present invention can be any molecule possessing biological activity, including, but not limited to small molecule drugs, proteins, peptides and antigens.
  • the mild reaction conditions utilized in the preparation of the composition of the instant invention provide a facile and easy formulation.
  • the present invention finds particular utility in the formulation of proteins, peptides, and antigens, where high heat conditions varying from physiological conditions can cause a partial, if not total loss of bioactivity.
  • bioactive agents which can be utilized in the present invention thus include, but are not limited to antiarthritics, antacids, anti-inflammatory substance, (including but not limited to non-steroidal anti- inflammatory drugs, NSAIDs, vasodilators, coronary vasodilators, and peripheral vasodilators), anti-infectives, psychotropics, antimanics, stimulants, antihistamines, laxatives, decongestants, vitamins, gastrointestinal sedatives, anti-diarrheal preparations, anti-anginal drugs, anti-arrhythmics, anti-hypertensive drugs, vasoconstrictors and migraine treatments, anticoagulants, and anti-thrombotic drugs, analgesics, anti-pyretics, hypnotics, sedatives, anti-emetics, anti-nauseants, anticonvulsants, neuromuscular drugs, hyper- and hypoglycemic agents, thyroid and antithyroid preparations, diuretics, b-block
  • the bioactive agents must be physically and chemically compatible with the polar polymer or monomer, as well as with the poly(acrylic acid) polymer utilized in the present invention.
  • the active medicament will be at least very slightly soluble in water, and more preferably, slightly soluble in water (as defined in Remingto 's Pharmaceutical Sciences, X 8 th edition, Chapter 16, page 208).
  • bioactive peptides and peptidiomimetics include, but not limited to, TRH, DDAVP, LHRH agonists, LHRH agonists, DADLE, metkephamid, oxytocin, insulin-like growth factors, growth hormone releasing factor, sleep inducing peptide, opiate antagonists, opiate agonists, DGAVP, somatostatin, peptide T, vasoactive intestinal polypeptide, gastric inhibitory peptide, cholecystokin and its active fragments, gastrin releasing peptide, ACTH and its analogues, and enkephalins.
  • bioactive proteins include, but not limited to, growth hormones, interferons, interleukins, calcitonin, insulin-like growth factors, insulin, colony stimulating factor, tumor inhibitory factors, transforming growth factors, epidermal growth factor, atrial naturetic factor, proinsulin, nerve growth factor, calcitonin, transforming growth factor beta, and glucagon.
  • Specific representative antigens include, but are not limited to, self-antigens and nonself-antigens implicated in autoimmune diseases, and their effective tolerogenic fragments, such as insulin, glutamic acid decarboxylase, heat shock protein 65, bovine serum albumin, carboxypeptidase H, ICA-69, type II collagen and its effective tolerogenic fragments, myelin basic protein and its effective tolerogenic fragments, and many others implicated in autoimmune diseases.
  • the autoimmune diseases include, but not limited to, systemic lupus erythematosus, dermatomyositis, Sydenham's chorea, rheumatoid arthritis, rheumatic fever, thrombocytopenic purpura, polyglandular syndromes, bullous pemphigoid, diabetes mellitus, henoch-schonlein purpura, post-streptococcal nephritis, systemic lupus erythematosus, erythema nodosum, Takayasu's arteritis, myasthenia gravis, thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, multiple sclerosis, sarcoidosis, ulcerative colitis, erythema multiforme, IgA nephropathy, polyarteritis nodosa.
  • ankylosing spondylitis goodpasture's syndrome, thromboangiitis obliterans, Sjogren's syndrome, primary biliary cirrhosis, thyrotoxicosis, scleroderma, chronic active hepatitis, polymyositis/dermatocyositis, polychondritis, pemphigus vulgaris, Wegener's granulomatosis, Henoch-Schonlein purpura, membranous nephropathy, amyotrophic lateral sclerosis, tabes forsalls, giant cell arteritis/polymyalgia, pernicious anemia, bullous pemphigoid, rapidly progressive glomerulonephritis, myasthenia gravis and fibrosing alveolitis.
  • Examples of specific active medicaments include aluminum hydroxide, prednisolone, dexamethasone, aspirin, acetaminophen, ibuprofen, isosorbide dinitrate, nicotinic acid, tetracycline, ampicillin, dexbrompheniramine, chlorpheniramine.
  • albuterol pseudoephedrine, loratadine theophylline, ascorbic acid, tocopherol, pyridoxine, metoclopramide, magnesium hydroxide, verapamil, procainamide hydrochloride, propranolol, captopril, ergotamine, flurazopam, diazepam, lithium carbonate, insulin, furosemide, hydrochlorothiazide, guaiphenesin, dextromethorphan, triamterene, diltiazem and benzocaine, although any active medicament which is physically and chemically compatible with the water-soluble polymer or monomer and poly (acrylic acid) polymer may be used in the present invention.
  • the weight percentage of the bioactive agent loaded into the matrix of the present invention ranges from 0.01% to 80%, preferably from 0.1 % to 80%, and most preferably, from about 1-35%), by weight of total composition.
  • the weight percentage of drug loading depends upon the particular bioactive agent, and the desired dose to be administered within the time period.
  • the poly(acrylic acid) polymer and the polar polymer are mixed in water or an aqueous miscible solvent such as ethanol, glycerol, polyethylene glycol, glycol or mixtures thereof.
  • the weight%> of the polymer mixture in the solution is in the range of about 0.05 to about 95% W/W, preferably about 0.5 to about 80% W/W, and most preferably about 0.5 to about 5%> W/W, and then the bioactive agent is added.
  • the amount ratio of poly(acrylic acid) to the polar polymer or monomer can range from 1 :90 to 90: 1, depending on the desired release pattern of the bioactive agent.
  • the ratio is from 20:80 to 80:20, and most preferably from 1 :10 to 10:1, but this can vary depending upon the particular poly(acrylic acid) and the polar polymer or monomer utilized in the composition.
  • a base which ionizes at a pH below 8, including but not limited to basic amino acids, such as lysine, polylysine, histidine, and arginine is added to modify the release profile of cationic pharmaceutical active agents to create individual unique release rates and durations.
  • the weight % of a base is in the range of 1-40%), based on the weight of the total composition.
  • a solution of the poly(acrylic acid) and a polar polymer or monomer containing the bioactive agent is spray-dried onto a support, such as a sugar seed or other support particle, a tablet, the surface of a baking or supporting layer of a transdermal or buccal patch, or an insert.
  • a heating temperature ranging from 37 °C to 1 10°C is applied during the spraying process, depending on the nature of the composition and bioactive agent.
  • the temperature is less than about 120°C, more preferably from about 37°C to 120°C, and most preferably, between 37°C to 80°C.
  • the solution of the polymer mixture can be spray-dried onto a surface to form a solid matrix layer in an automated system .
  • the solid matrix composition can be formed as a flake, pellet, spheres, or irregular particulate.
  • the solid matrix composition can be formed into tablets or capsules or other pharmaceutical dosage forms using standard pharmaceutical procedures, optionally, using additional inactive pharmaceutical excipients such as binders, diluents, and disintegrants, for making the tablets, capsules or other pharmaceutical dosage forms.
  • the solution of the polymer mixture can be spray-dried onto sugar/starch seeds in a conventional coating pan as indicated, or alternatively, using an automated system such as a CF granulator, for example, a FREUND® CF granulator. a GLATT® fluidized bed processor, an AEROMATIC®, a modified ACCELA-COTA® or any other suitably automated bead coating equipment to form particulates or particles or granules of about 0.1 mm or larger. In these spraying processes, the above-noted thermal ranges apply.
  • the solid matrix composition can additionally include an enteric or pH-dependent or enzyme-sensitive (such as azopolymer) coating to control the release at a certain site in the GI tract.
  • an enteric or pH-dependent or enzyme- sensitive such as azopolymer
  • the solid matrix composition can be adapted for intranasal, oral, buccal, intratracheal, transdermal, vaginal or rectal administration.
  • plasticizers i.e., either small molecules or large molecules often used to change the permeability of polymer films, can also be included to manipulate the release rate of the bioactive agent from the polymer blend matrix.
  • useful plasticizers include, but not limited to, organic plasticizers with low molecular weight, such as glycerol, glycerol monoacetate, glycerol diacetate, glycerol triacetate; low molecular polyalkylene oxides, such as polyethylene oxide, polyethylene-propylene glycols, polypropylene glycols; diethyl phthalate, propylene glycol, sodium diethylsulfosuccinate, sorbitol, tributyl citrate, and triethylcitrate.
  • Preferred plasticizers include propylene glycol, sorbitol, triethylcitrate.
  • the weight percentage of plasticizer ranges from 0.5 to 50 weight %, and most preferably 0.5 to 30 weight %>, by weight of total composition.
  • Other excipients, such as coloring agents, lubricants, binders, disintegrants, and flavorings may also be added at the discretion of the skilled pharmaceutical formulator.
  • protective excipients which are able to inhibit lumenal degradation of these sensitive agents in the intestine are preferably added to the polymer blends.
  • excipients include, but are not limited to, organic acids.
  • organic acids are citric acid and malic acid.
  • the weight %> of the organic acid is 1% to 30%, and most preferably, 1-5%), by weight of total composition.
  • EXAMPLE 1 The following suspensions were prepared: Carbopol 97 IP (0.15 g) and hydroxyethyl cellulose (0.15 g) suspended in 30 ml water, Carbopol 971 P (0.3 g) and hydroxyethyl cellulose (0.3 g) suspended in 15 ml ethanol, Carbopol 971P (0.6 g) and hydroxyethyl cellulose (0.6 g) suspended in 15 ml ethanol, Carbopol 971 P (0.15 g) and hydroxypropyl cellulose (0.15 g) suspended in 30 ml water, and Carbopol 971P (0.3 g) and hydroxypropyl cellulose (0.3 g) suspended in 15 ml ethanol.
  • Aluminum pans with a diameter of 7.5 cm and 3 cm were used for 30 ml and 15 ml of each suspension, respectively.
  • a drying temperature of 60°C, 80°C, and 100°C was applied to a suspension.
  • the resulting gel film from each suspension at a drying temperature was then soaked in water for more than 48 hours.
  • Three suspensions of each kind were each dried at a temperature.
  • the gel films from all suspensions dried at each temperature remained intact after 48 hours soaking.
  • Carbopol 971P (0.15 g) and a polar polymer or monomer (0.15g) were suspended in 30 ml water.
  • the suspension was poured into a aluminum pan with a diameter of 7.5 cm and then vacuum dried at 40°C over 48 hours.
  • the films obtained was then soaked in 100 ml water.
  • the film was weighed before and after soaking in water. After swelling for 1 hour, the firmness of gel film was judged visually and touching with forceps. The results are summarized in Table 1 below.
  • Carbopol® 97 IP 0.15 g
  • the gel film was firm when the drying Natrosol®: 0.15 g temperature was equal to or greater than 37 °C. The gel swelled upon hydration.
  • Carbopol® 97 IP 0.15g
  • the gel film was firm when the drying Propylene glycol alginate: 0.15 g temperature was equal to or greater than 40°C. The gel swelled upon hydration.
  • Carbopol® 97 IP 0.15g
  • the gel film was firm when the drying D-mannitol: 0.15 g temperature was equal to or greater than 40°C. The gel swelled upon hydration.
  • Carbopol® 971P 0.15g No firm gel film with a defined shape was Polyvinylalcohol : 0.15 g formed at 40°C. The gel mass was loose and dissipated once hydrated.
  • Carbopol® 971P 0.15g No firm gel film with a defined shape was Polyvinylpyrrolidone: 0.15 g formed at 40°C. The gel mass was loose.
  • Carbopol® 971P 0.15g No firm gel film with a defined shape was Hydroxypropylmethylcellulose formed at 40°C. The gel mass was loose.
  • Carbopol® 971 P 0.15g No firm gel film with a defined shape was Hydroxypropylmethylcellulose formed at 40°C. The gel mass was loose.
  • Carbopol® 97 IP 0.15 ⁇ No firm gel film with a defined shape was Eudragit S-100 formed at 100°C. The gel mass was loose and dissipated once hydrated.
  • Carbopol® 97 IP 0.15g No firm gel film with a defined shape was Eudragit® LI 00 formed at 100°C. The gel mass was loose and dissipated once hydrated.
  • Natrosol®(99-250 L NF) is a commercially available hydroxyethylcellulose.
  • EXAMPLE 3 Each of hydroxypropylcellulose (0.15g), carboxymethylcellulose(0.15g), hydroxyethylcelluose (0.15g), and propylene glycol alginate (0.15g) was mixed with 0.15 g Carbopol® 97 IP NF in 30 ml water, and then dried at various temperatures for 48 hours under vacuum. The drying temperature for the hydroxypropylcellulose mixture was 100°C, for the carboxymethylcellulose mixture, 40°C, for propylene glycol alginate mixture, 100°C, and for hydroxyethylcellulose mixture, 100°C.
  • Polymer Blend Swelling hydroxypropylcellulose (100°C) 725% carboxymethylcellulose (40°C) 2283 % hydroxyethylcelluose (100°C) 259% propylene glycol alginate (100°C) 450 % hydroxyethylcelluose (60°C) 3600%
  • Insulin-FITC (2 mg), Carbopol® 971P NF (100 mg), and hydroxyethylcelluose (100 mg) were suspended in 15 ml ethanol and then dried in aluminum pan of a diameter of 3 cm at 37°C for 48 hours.
  • Insulin-FITC (M.W.: 6,380) is bovine pancreas insulin coupled to fluorescein isothiocyanate.
  • the release of insulin-FITC in pH 7.5 phosphate buffer (250 ml) was studied over a 24 hour period using a water bath shaker (Prevision) at 37°C with a shaking frequency of 90 rpm.
  • Insulin-FITC was quantified using a UV/visible spectrophotometer (Genesys® 2, Fisher Scientific) at 495 nm. The results of the percentage of insulin released from over time of this formulation are shown in FIGURES 1A and IB.
  • EXAMPLE 5 Carbopol® 971P NF (0.6 g), hydroxyethylcellulose (0.6g ), and diltiazem (0.015 g) were mixed in 15 ml ethanol and then dried as described in Example 1. The release of diltiazem was studied in 30 ml pH 7.5 phosphate buffer as described in Example 2. The concentration of diltiazem in sampled aliquot was determined at 290 nm. The results are summarized in FIGURE 2. A controlled release of diltiazem was completed by 97 hours.
  • Triamterene formulated in the polymer blend of Carbopol® 97 IP NF and hydroxyethylcellulose was as described in Example 5.
  • the release profile of triamterene from this polymer blend matrix over time is shown graphically in FIGURE 3.
  • EXAMPLE 8 Diltiazem formulated in the polymer blend of Carbopol 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release profile of diltiazem at a loading of 67% is shown in Table 4.
  • EXAMPLE 9 Diltiazem formulated in the polymer blend of Carbopol 97 IP NF and hydroxyethylcellulose was as described in Example 5. The release of diltiazem was affected by the addition of lysine to the composition. The results are listed in Table 5 below.
  • composition Rate of release (mg /hr)
  • Carbopol 971P 0.3 g
  • Carbopol® 974P 0.3 g
  • Carbopol® 934P hydroxyethylcellulose
  • EXAMPLE 1 1 Dextran (Sigma) (0.3g) was mixed with Carbopol® 971P NF (0.3g) in 30 ml water and dried at 60 °C. The gel film was transparent and able to maintain its shape after several hours' soaking in water.
  • Carbopol (0.4%o (W/V) and citric acid (12 mM) or maleic acid (20 mM) were dissolved in intestinal fluid.
  • the degradation of insulin in simulated intestinal fluid was studied at 37°C using the TCA method and iodinated insulin (Amershan).
  • the results of protection of insulin from degradation by intestinal enzymes by various combinations of organic acid and Carbopol® polymers are summarized in the following Table 5.

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Abstract

La présente invention concerne un système de matrice à libération contrôlée comportant un mélange d'acide poly(acrylique) et d'un polymère ou d'un monomère polaire ledit polymère ou monomère polaire présentant un rapport carbone-oxygène inférieur ou égal à 1,9/1, et un rapport carbone-groupe hydroxyle de 5/1, le rapport en poids dudit acide poly(acrylique) audit polymère ou monomère polaire étant compris entre 10/90 et 90/10; ce système est utilisé pour l'administration d'agents pharmaceutiques.
PCT/US1997/021280 1996-11-20 1997-11-20 Composition d'une matrice a liberation controlee utilisant un melange d'acide poly(acrylique) et d'un polymere ou d'un monomere polaire WO1998022097A2 (fr)

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US6284235B1 (en) * 2000-02-11 2001-09-04 National Starch And Chemical Company Investment Holding Corporation Bioadhesive composition
WO2001082895A2 (fr) * 2000-04-28 2001-11-08 Adams Laboratories, Inc. Formulation et comprimes de liberation soutenue de guaifenesine
WO2003006993A2 (fr) * 2001-07-10 2003-01-23 De Montfort University Compositions de gel
WO2003063839A1 (fr) 2002-01-31 2003-08-07 National Starch And Chemical Investment Holding Corporation Composition de bioadhesif comprenant un polysaccharide et un polymere polycarboxyle
WO2005056648A1 (fr) 2003-12-12 2005-06-23 Lts Lohmann Therapie-Systeme Ag Forme galenique a base de polymeres hydrophiles reticules
US6955821B2 (en) 2000-04-28 2005-10-18 Adams Laboratories, Inc. Sustained release formulations of guaifenesin and additional drug ingredients
EP1579854B1 (fr) * 2004-03-10 2011-08-03 Acino AG Système thérapeutique dermal ou transdermal comprénant une matrice constituée par un matériau recroissant
WO2015156990A1 (fr) * 2014-04-08 2015-10-15 Teikoku Pharma Usa, Inc. Compositions transdermiques à base de rivastigmine et leurs méthodes d'utilisation
WO2017027378A1 (fr) * 2015-08-07 2017-02-16 Xcede Technologies, Inc. Compositions adhésives et procédés associés
US9833538B2 (en) 2015-08-07 2017-12-05 Xcede Technologies, Inc. Adhesive compositions and related methods
US9956311B2 (en) 2012-02-03 2018-05-01 Xcede Technologies, Inc. Tissue patch
US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US11357722B2 (en) 2011-02-04 2022-06-14 Seed Health, Inc. Method and system for preventing sore throat in humans
US11826388B2 (en) 2013-12-20 2023-11-28 Seed Health, Inc. Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation
US11833177B2 (en) 2013-12-20 2023-12-05 Seed Health, Inc. Probiotic to enhance an individual's skin microbiome
US11839632B2 (en) 2013-12-20 2023-12-12 Seed Health, Inc. Topical application of CRISPR-modified bacteria to treat acne vulgaris
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US11951140B2 (en) 2011-02-04 2024-04-09 Seed Health, Inc. Modulation of an individual's gut microbiome to address osteoporosis and bone disease
US11969445B2 (en) 2013-12-20 2024-04-30 Seed Health, Inc. Probiotic composition and method for controlling excess weight, obesity, NAFLD and NASH
US11980643B2 (en) 2013-12-20 2024-05-14 Seed Health, Inc. Method and system to modify an individual's gut-brain axis to provide neurocognitive protection
US11998479B2 (en) 2011-02-04 2024-06-04 Seed Health, Inc. Method and system for addressing adverse effects on the oral microbiome and restoring gingival health caused by sodium lauryl sulphate exposure
US11998574B2 (en) 2013-12-20 2024-06-04 Seed Health, Inc. Method and system for modulating an individual's skin microbiome
US12005085B2 (en) 2013-12-20 2024-06-11 Seed Health, Inc. Probiotic method and composition for maintaining a healthy vaginal microbiome

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US9549842B2 (en) 2011-02-04 2017-01-24 Joseph E. Kovarik Buccal bioadhesive strip and method of treating snoring and sleep apnea
US11844720B2 (en) 2011-02-04 2023-12-19 Seed Health, Inc. Method and system to reduce the likelihood of dental caries and halitosis

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EP0159604A2 (fr) * 1984-04-09 1985-10-30 Toyo Boseki Kabushiki Kaisha Préparation à libération retardée applicable aux muqueuses de la cavité buccale
FR2582942A1 (fr) * 1985-06-05 1986-12-12 Yamanouchi Trading Co Ltd Rubans medicaux adhesifs pour la muqueuse buccale
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US6824792B2 (en) 2000-02-11 2004-11-30 Universiteit Gent Bioadhesive composition
US6284235B1 (en) * 2000-02-11 2001-09-04 National Starch And Chemical Company Investment Holding Corporation Bioadhesive composition
AU2001255680B2 (en) * 2000-04-28 2006-02-16 Rb Health (Us) Llc Guaifenesin sustained release formulation and tablets
WO2001082895A3 (fr) * 2000-04-28 2002-05-23 Adams Lab Inc Formulation et comprimes de liberation soutenue de guaifenesine
US6955821B2 (en) 2000-04-28 2005-10-18 Adams Laboratories, Inc. Sustained release formulations of guaifenesin and additional drug ingredients
WO2001082895A2 (fr) * 2000-04-28 2001-11-08 Adams Laboratories, Inc. Formulation et comprimes de liberation soutenue de guaifenesine
EP1913937A1 (fr) * 2000-04-28 2008-04-23 Adams Respiratory Operations, Inc. Formules à libération prolongée de guaifenésine, et comprimés
WO2003006993A2 (fr) * 2001-07-10 2003-01-23 De Montfort University Compositions de gel
WO2003006993A3 (fr) * 2001-07-10 2003-09-25 Univ Montfort Compositions de gel
US8247391B2 (en) 2001-07-10 2012-08-21 De Montfort University Gel compositions
WO2003063839A1 (fr) 2002-01-31 2003-08-07 National Starch And Chemical Investment Holding Corporation Composition de bioadhesif comprenant un polysaccharide et un polymere polycarboxyle
US7846478B2 (en) 2002-01-31 2010-12-07 Henkel Ag & Co. Kgaa Bioadhesive composition
WO2005056648A1 (fr) 2003-12-12 2005-06-23 Lts Lohmann Therapie-Systeme Ag Forme galenique a base de polymeres hydrophiles reticules
CN100425639C (zh) * 2003-12-12 2008-10-15 Lts勒曼治疗系统股份公司 基于交联的亲水性聚合物的给药方式
EP1579854B1 (fr) * 2004-03-10 2011-08-03 Acino AG Système thérapeutique dermal ou transdermal comprénant une matrice constituée par un matériau recroissant
US11357722B2 (en) 2011-02-04 2022-06-14 Seed Health, Inc. Method and system for preventing sore throat in humans
US11998479B2 (en) 2011-02-04 2024-06-04 Seed Health, Inc. Method and system for addressing adverse effects on the oral microbiome and restoring gingival health caused by sodium lauryl sulphate exposure
US11951140B2 (en) 2011-02-04 2024-04-09 Seed Health, Inc. Modulation of an individual's gut microbiome to address osteoporosis and bone disease
US9956311B2 (en) 2012-02-03 2018-05-01 Xcede Technologies, Inc. Tissue patch
US11833177B2 (en) 2013-12-20 2023-12-05 Seed Health, Inc. Probiotic to enhance an individual's skin microbiome
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US11998574B2 (en) 2013-12-20 2024-06-04 Seed Health, Inc. Method and system for modulating an individual's skin microbiome
US11980643B2 (en) 2013-12-20 2024-05-14 Seed Health, Inc. Method and system to modify an individual's gut-brain axis to provide neurocognitive protection
US11969445B2 (en) 2013-12-20 2024-04-30 Seed Health, Inc. Probiotic composition and method for controlling excess weight, obesity, NAFLD and NASH
US11839632B2 (en) 2013-12-20 2023-12-12 Seed Health, Inc. Topical application of CRISPR-modified bacteria to treat acne vulgaris
US11826388B2 (en) 2013-12-20 2023-11-28 Seed Health, Inc. Topical application of Lactobacillus crispatus to ameliorate barrier damage and inflammation
WO2015156990A1 (fr) * 2014-04-08 2015-10-15 Teikoku Pharma Usa, Inc. Compositions transdermiques à base de rivastigmine et leurs méthodes d'utilisation
US10357463B2 (en) 2014-04-08 2019-07-23 Teikoku Pharma Usa, Inc. Rivastigmine transdermal compositions and methods of using the same
US9949935B2 (en) 2014-04-08 2018-04-24 Teikoku Pharma Usa, Inc. Rivastigmine transdermal compositions and methods of using the same
WO2017027378A1 (fr) * 2015-08-07 2017-02-16 Xcede Technologies, Inc. Compositions adhésives et procédés associés
US10722611B2 (en) 2015-08-07 2020-07-28 Xcede Technologies, Inc. Adhesive compositions and related methods
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US11278506B2 (en) 2015-10-09 2022-03-22 Rb Health (Us) Llc Pharmaceutical formulation
US11951139B2 (en) 2015-11-30 2024-04-09 Seed Health, Inc. Method and system for reducing the likelihood of osteoporosis

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