WO1992015285A1 - Compositions a liberation regulee a base d'amidon - Google Patents

Compositions a liberation regulee a base d'amidon Download PDF

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Publication number
WO1992015285A1
WO1992015285A1 PCT/US1992/001762 US9201762W WO9215285A1 WO 1992015285 A1 WO1992015285 A1 WO 1992015285A1 US 9201762 W US9201762 W US 9201762W WO 9215285 A1 WO9215285 A1 WO 9215285A1
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WO
WIPO (PCT)
Prior art keywords
starch
composition
agents
matrix
drugs
Prior art date
Application number
PCT/US1992/001762
Other languages
English (en)
Inventor
David J. Lentz
Antonio Moroni
Kuchi S. Murthy
Galen W. Radebaugh
Mahdi Fawzi
Michael G. Williams
Subraman Rao Cherukuri
Tsun-Ming Chen
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Warner-Lambert Company
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Publication of WO1992015285A1 publication Critical patent/WO1992015285A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • This invention relates to controlled release therapeutic compositions which are capable of delivering 0 their therapeutic active or agent over a predetermined period of time. These compositions may be used wherever controlled release is desired, i.e., in medicine, food, agriculture and the like. More particularly, this invention relates to sustained release compositions as " well as those which require fast or moderate release periods of the active.
  • sustained release dosage forms are well known. Among the most important advantages are: (1) increased contact time for the drug to allow for local activity in the stomach, intestine or other locus of activity; (2) increased and more efficient absorption for drugs which have specific absorption- sites; (3) the ability to reduce the number of dosages per period of time; (4) employment of less total drug; (5) minimization or elimination of local and/or systemic side effects; (6) minimization of drug accumulation associated with chronic dosing; (7) improved efficiency and safety of treatment; (8) reduced fluctuation of drug level; and (9) better patient compliance with overall disease management.
  • sustained release drug delivery has many important non-therapeutic ramifications as well, including a financial saving to the patient in terms of less lost work days, less hospitalization and fewer visits to the physician.
  • SR sustained release
  • polymeric capsules with a solid, liquid, suspension or gel containing a therapeutic agent which is slowly released by diffusion through the capsule walls.
  • Heterogeneous matrices for example compressed tablets, control the release of their therapeutic agents either by diffusion, erosion of the matrix or a combination of both.
  • Other SR systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on diffusion or erosion to control release of the therapeutic agent.
  • Liquid- iquid encapsulations whereby a liquid therapeutic agent is encapsulated in a viscous syrup-like solution of polymer, have also been known to be useful in controlling release of the therapeutic agent. Additionally, it is generally known that heterogeneous dispersions or solutions of therapeutic agents in water-swellable hydrogel matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the agent from the water-swollen part of the matrix.
  • the dosage form During dissolution of a controlled release matrix tablet, the dosage form generally remains as a non-disintegrating, slowly eroding entity from which the therapeutic agent leaches out, through a diffusion controlled process.
  • Conventional SR formulations are generally designed to release their actives over an extended period of time, usually 8-24 hours.
  • Conventional SR formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active ingredients.
  • the drug is dispersed in the wax matrix in the molten state.
  • One disadvantage of this method is that decomposition and/or crystalline transformation of the drug may occur, thereby rendering the drug less effective as a therapeutic agent.
  • waxes and waxy materials used in pharmaceutical formulations are carnauba wax, spermaceti wax, candellila- wax, cocoa butter, cetosteryl alcohol, beeswax, partially hydrogenated vegetable oils, ceresin, paraffin, myristyl alcohol, stearyl alcohol, cetylalcohol and stearic acid. They are generally used in amounts of about 10 to about 50% by weight of the total formulation. Hydrophilic gums have also been known to be reasonably effective as SR carriers for both high-dose and low-dose drugs.
  • Typical hydrophilic gums used as SR carrier materials are acacia, gelatin, tragacanth, veegum, xanthan gum, carboxymethyl cellulose (CMC), hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and hydroxyethyl cellulose (HEC). Generally these materials are present in amounts of about 10 to 50% by weight of the final formulation.
  • Starch USP (potato or corn) is commonly used as a component in conventional tablet or hard shell capsule formulations. It generally functions in conventional applications as a diluent or as a disintegrant in oral dosage forms. Starch paste is also often used as a binder in these products.
  • modified starches such as carboxymethyl starch currently marketed under the trade name Explotab or Primojel are used both in tablets and capsules as disintegrating agents. The literature discloses that native and modified starches are useful in promoting rapid release of drugs from solid oral dosage forms. Additionally, native starch has been used in some instances as a binder to produce granulations of active drug substances.
  • pregelatinized starch has been reported as being useful as an SR matrix for theophylline formulations by Herman and Remon, "Modified Starches as Hydrophilic Matrices for Controlled Oral Delivery; III Evaluation of Sustained-Release Theophylline Formulations Based on Thermal Modified Starch Matrices in Dogs," in International Journal of- Pharmaceutics, 63 (1990) 201-205.
  • modified starch were mixed with anhydrous theophylline (60:40 W/W) as well as with silicon dioxide (Aerosil 200) and sodium benzoate.
  • Theodur 300 is the trade name for a commercially available sustained release theophylline product. This system comprises theophylline coated onto sugar beads, which beads are then encapsulated with lipids, such as glyceryl monostearate, cetyl alcohol, beeswax, shellac and/or an acid resistant polymer such as cellulose acetate phthalate. The encapsulated beads are then compressed into a matrix containing the drug.
  • lipids such as glyceryl monostearate, cetyl alcohol, beeswax, shellac and/or an acid resistant polymer such as cellulose acetate phthalate.
  • Pregelatinized starch is defined in the National Formulary XVII (1990) as starch which has been chemically and/or mechanically processed to rupture all or part of the granules in the presence of water and subsequently dried. Typically this is done by cooking and mixing an aqueous slurry of starch for a predetermined time until the granular structure of the starch is physically distorted or partially broken apart. This does not result in any significant change in the molecular structure of the starch. m
  • Starch 1500 a pre-gelatinized starch marketed by Colorcon, Inc.
  • Merigel XX marketed by Amylum, a Belgian Company.
  • prior art systems have included starch for various purposes in pharmaceutical products. Most of these uses do not show sustained release properties and with few exceptions has starch demonstrated any particular advantages or benefits.
  • the instant invention overcomes the disadvantages of the prior art by offering a relatively simple and inexpensive means of obtaining controlled release through the use of a natural, biocompatable material which is obtainable through a renewable resource.
  • starch can be rendered destructurized without degradation. This means that the granular structure has been substantially broken down. Depending on the parameters used to obtain overall destructurization, a variety of levels or degrees of destructurization can be reached. At each level, however, a substantial amount of the starch is in the molecularly dispersed form whereby the granular structure (starch granules) normally present in native or gelatinized starch is substantially destroyed, as evidenced by observation using conventional optical microscopy.
  • destructurized starch are significantly different from those of pregelatinized starch and include the ability to be melted and reformed using standard extrusion techniques normally employed for thermoplastic polymers. Starch which has been destructurized in this manner can be said to be thermoplastic in nature.
  • destructurized starch has been used in injection molding applications, extrusion applications and combined with various polymers and other additives to make finished products.
  • injection molded capsules have been made from destructurized starch.
  • MDS molecularly dispersed starch
  • Figure 1 illustrates the dissolution profile of tacrine HCI tablets made from the inventive composition of Example 1 as compared to the conventional compositions of Examples 2 and 3.
  • Figure 2 illustrates the effect of different dissolution media on the inventive composition of Example 1.
  • Figure 3 graphically depicts the 24 hour release profile using both conventional USP recommended apparata, i.e. the paddle apparatus and the basket apparatus.
  • Figure 4 illustrates 24 hour release profiles of the inventive composition of Examples 4 and 5 wherein the lubricants magnesium stearate and glyceryl behenate are used. Also shown is the release profile for Example 1 which does not include lubricants.
  • FIG 5 graphically shows the 24 hour profile of several different dose strengths of tacrine HCI, per inventive tablet (Examples 1 and 6).
  • Figure 6 illustrates the effects of moisture level on the 24 release profiles of the inventive composition- of Example 1.
  • Figure 7 is a dissolution graph of capsules containing gemfibrozil in the inventive matrix and a conventional corn starch carrier, respectively.
  • Figure 8 is a dissolution graph of capsules containing tacrine HCI and comparing the inventive matrix with a native corn starch carrier.
  • Figure 9 is a dissolution graph showing the results of using two different dissolution apparati.
  • Figure 10 is a dissolution graph of tacrine HCI as a function of the different levels of starch destructurization.
  • Figure 11 is a dissolution graph showing the effect of pancreatin USP in the media on the inventive matrix.
  • Figure 12 is a dissolution graph comparing the release profiles of the inventive matrix with ' commercially available pregelatinized starch.
  • Figure 13 is a dissolution graph showing the effect of the lubricant sodium benzoate on the inventive matrix as compared to pregelatinized starch.
  • Figure 14 is a dissolution graph showing the effect of the lubricant magnesium stearate on the inventive matrix as compared to pregelatinized starch.
  • Figure 15 is a dissolution graph comparing the SR profiles of the inventive matrix with pregelatinized starch.
  • Figure 16 is a graph showing a typical desired release profile for oral sustained release products.
  • Figure 17 is a graph showing the results of. incorporating a carbonate salt excipient into a formulation comprising destructurized starch.
  • Figure 18 shows the dissolution rates of diphenhydramine in formulations containing different types of starch.
  • Figure 19 shows the dissolution rates of ibuprofin in formulations containing different types of starch.
  • Figure 20 shows the dissolution rates of phenytoin sodium in formulations containing different types of starch.
  • Figure 21 shows the dissolution rates of gemfibrozil in formulations containing different types of starch in a pH 7.5 buffer with enzymes.
  • Figure 22 shows the dissolution rates of gemfibrozil " in formulations containing different types of starch in a pH 7-5 buffer.
  • Figure 23 shows the dissolution rates of gemfibrozil in formulations containing destructurized starch and differing amounts of gemfibrozil in a pH 7.5 buffer with enzymes.
  • Figure 24 shows the dissolution rates of gemfibrozil in formulations containing destructurized starch and differing amounts of gemfibrozil in a pH 7.5 buffer.
  • Figure 25 shows the dissolution rates of gemfibrozil in formulations containing destructurized starch and various amounts of sodium carbonate in a pH 7.5 buffer.
  • Figure 26 shows the dissolution rates of gemfibrozil in formulations containing destructurized starch and magnesium carbonate or sodium carbonate in pH 7.5 buffer with enzymes.
  • Figure 27 shows the dissolution rates of gemfibrozil in formulations containing destructurized starch and magnesium carbonate or sodium carbonate in pH 7.5 buffer.
  • the invention concerns the use of starch which has been processed under specific conditions in order to Q render it suitable as a sustain release (SR) or controlled release (CR) matrix when combined with therapeutic agents and other chemical entities which are intended to be controllably released. More particularly, the instant invention relates to controlled release pharmaceutical compositions comprising (i) a matrix comprising starch which has been processed under shear at temperatures of about 80°C to about 240°C in a closed volume wherein the water content of said starch is maintained at about 5% to about 45% by weight based on the starch/water mix and (ii) a pharmaceutically active ingredient, wherein said matrix is in intimate contact with said active ingredient and wherein said matrix and said pharmaceutically active ingredient are present in amounts sufficient to control the release of the pharmaceutically active ingredient in an effective dose.
  • Starch which has been processed under these conditions has been found to be substantially free from intact starch granular structure and is said to be destructurized or in the molecularly dispersed state.
  • destructurized starch molecularly dispersed starch (MDS) and thermoplastic starch will be used interchangeably.
  • MDS molecularly dispersed starch
  • thermoplastic starch thermoplastic starch
  • starch melts which may be used as controlled release matrices.
  • Starch melts processed in the parameters set forth herein generally have a substantial disruption of the granular structure.
  • Starch melts processed at the lower end of the processing parameters can be considered an early or first level of destructurization. As the melt becomes more uniform, the disruption of the granular structure becomes even more evident, yielding a second level of destructurization.
  • a third level of destructurization involves heating the melt above the glass transition temperature and melting point of the ingredients. At this level the melt is clearly a thermoplastic material. " The last level of destructurized starch involves the formation of a molecularly dispersed starch. At this level, the melt has been heated to a high enough temperature for a sufficient time so that the specific endothermic transition analysis as represented by a differential scanning calorimetry curve indicates that a specific relatively narrow peak just prior to oxidation and thermal degradation has disappeared.
  • starch melt or "molten starch” when used herein to describe the inventive compositions will mean starch which has been processed in accordance with the parameters given.
  • active ingredient will include, but not be limited to, pharmaceutically active ingredients, such as drugs, medicaments, therapeutic agents and other chemicals or materials useful in treatment of mammals, other animals, insects, fish and plants.
  • pharmaceutically active ingredients such as drugs, medicaments, therapeutic agents and other chemicals or materials useful in treatment of mammals, other animals, insects, fish and plants.
  • this term will include non-ingestible materials and chemicals which are useful in, for example, agricultural applications, and ingestible materials for food applications and numerous other applications where the active ingredient is to be released into the surrounding environment via the inventive matrix.
  • This invention also relates to a controlled release therapeutic composition
  • a controlled release therapeutic composition comprising (i) a matrix of starch being substantially free of intact starch granules; and (ii) a therapeutic agent.
  • the matrix can comprise destructurized starch and preferably molecularly
  • inventive compositions can be made by forming an admixture of (i) starch which has been processed to obtain a melt, e.g. under shear in a closed volume at temperatures of about 80° to about 240°C, and preferably about 130°C to about 160°C, while maintaining
  • An alternative method of preparing the inventive 20 compositions comprises mixing a therapeutic active with starch under sufficient conditions of temperature, shear and moisture to produce a controlled release composition.
  • U.S. Patent No. 4,673,4308 which patent is 25 incorporated herein by reference, discloses that natural starch (found in vegetable products) that contains a defined amount of water can be treated at an elevated temperature in a closed volume, and at elevated pressures, to form a melt.
  • the process is conveniently 30 carried out in an injection molding machine or extruder.
  • the starch is fed through a hopper onto a rotating, reciprocating screw.
  • the feed material moves along the screw toward the tip.
  • the temperature of the material is increased by means of " external heaters around the outside of the barrel and by the shearing action of the screw. Starting in the feed zone and continuing in the compression zone, the particulate starch feed becomes gradually molten.
  • the molten material at the tip can then be treated further by injection molding or extrusion or any other known technique to - treat thermoplastic melts, to obtain shaped articles.
  • the destructurized starch be heated to a high enough temperature and for a time sufficient so that the specific endothermic transition analysis as represented by a differential scanning calorimetry (DSC) curve indicates that a specific relatively narrow peak just prior to oxidation and thermal degradation has disappeared, as described in copending U.S. patent Application Serial Number 278,116, which is incorporated herein by reference.
  • DSC differential scanning calorimetry
  • the controlled release mechanism of the starch melt matrices used in the inventive compositions g is not completely understood, it is hypothesized that the formation of the melt allows for better compressibility and possibly denser tablet formation.
  • the increased compressibility and/or density of these matrices may contribute to the SR action of the composition.
  • Starches which are considered useful in the instant invention include starches obtained from natural sources " as well as chemically and physically modified starches.
  • Starch derived from corn, waxy maize, wheat, potato, rice, rye, oats, tapioca, pea, and the like are examples of natural starches which are useful in the instant invention.
  • Starches which are genetically or biologically modified are also useful.
  • water-soluble and water-insoluble drugs have been found to be useful in the delivery systems covered by the invention.
  • water-soluble and water-insoluble drug will have the following definitions.
  • Water-soluble drug will mean that up to 30 parts of solvent are required to completely dissolve 1 part of drug.
  • water-insoluble drug will mean greater than 30 parts of solvent are required to dissolve 1 part of the drug.
  • USP XXII page 1807 incorporated herein by reference.
  • the compositions can be used to obtain specific controlled release profiles, combining aspects of immediate release, intermediate release, and sustained release in one formulation. For example drugs falling into the following therapeutic categories are representative of those that could be used in combination with the novel delivery matrix.
  • ACE inhibitors include, but are not limited to, ACE inhibitors; anti-anginal drugs; anti-arrhythmias; anti-asthmatic; anti-cholesterolemic; _, anti-convulsants; anti-depressants; anti-diarrhea preparations; anti-histamines; anti-hypertensive drugs; anti-infectives; anti-inflamatory agents; anti-lipid agents; anti-manics; anti-nauseants; anti-stroke agents; anti-thyroid preparations; anti-tumor drugs; an i-tussives; anti-uricemic drugs; anti-viral agents; acne drugs; alkaloids; amino acid preparations; anabolic drugs; analgesics; anesthetics; antacids; antiarthritics; antibiotics; anticoagulants; antiemetics; antiobesity drugs; antiparasitics; antipsychotics; antipyretics; antispasmodics; antithrombotic drugs; anxio
  • compositions of the invention comprise a ratio of matrix to active ingredient sufficient to controllably release the active at an effective or desired rate and 0 amount.
  • this ratio may vary considerably, depending on the properties of the drugs involved, specific dosage form, process of preparation of the overall composition, S the addition of various additives, as well as other factors which may dictate a useful therapeutic ratio.
  • the amount of drug used may be as little as .05 mg per 100 mg tablet.
  • procainanide as much as 1000 mg per 1300 mg tablet may be used, representing a ratio of 0.3 to 1 of matrix to drug.
  • Another example of a high dose drug is gemfibrozil, which may be as much as 600 mg of drug in a 1 gram tablet, representing a ratio of about 1.0 to about 1.5.
  • the ratio of matrix to drug may range from about 5 to 95 to about 99.999 to 0.001, depending on the factors discussed above.
  • the ratio of matrix to drug is about 1 to 9 to about 9 to 1.
  • any ratio of matrix to pharmaceutically active ingredient which controls the release of the active at an effective rate and dose for the intended purpose is useful.
  • those starches useful in the matrix may be obtained from natural, modified or genetically engineered starches.
  • the starch may be destructurized prior to admixture" with the active ingredient or, if the active ingredient is sufficiently stable, the active ingredient may be added to the starch prior to destructurization and subsequently passed through the destructurization process.
  • the inventive compositions may use all of one type of starch or may use a combination of different starches to achieve different
  • Starch processing parameters vary within the aforesaid ranges of starch, water content, shear and temperature, as is known in the art. It should be noted, moreover, that it has recently been discovered that certain polyols, such as sorbitol, mannitol, xylitol and the like, may be substituted for or added in addition to some or all of the water in the destructurization of the starch. Although aqueous starch systems are preferred in achieving destructurization, other ingredients which may be found to be useful in achieving this end are contemplated.
  • the destructurized starch may also be essentially "free of bridged phosphate groups, which as disclosed in U.S. Patent 4,900,361, incorporated herein by reference, produces molded articles which have substantially less defects than those destructurized starches where the phosphate groups are bridged. This is accomplished by a process which substantially removes multivalent bridging ions and the free electrolytes associated therewith.
  • inventive matrix Due to the unique physical and chemical properties of the inventive matrix, it may be combined with a wide variety of pharmaceutically active ingredients having a wide range of chemical and therapeutic characteristics. For example, both highly water soluble active and highly water-insoluble actives have been found to be useful. More specifically, non-limiting specific examples of pharmaceutically acceptable actives can be chosen from the list which follows. Mixtures of these drugs and their salts used for appropriate therapies are also contemplated.
  • Pharmaceutically active compounds include, but are not limited to, acetaminophen; acetic acid; acetylsalicilic acid and its buffered form; albuterol and its sulfate; alcohol; allantoin; aloe; aluminum acetate, carbonate, chlorohydrate, hydroxide; alprozolam; amino acids; aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame; atenolol; bacitracin; balsam peru; beclomethasone dipropionate; benzocaine; benzoic acid; benzophenones benzoyl peroxide; biotin; bisacodyl; bornyl acetate bromopheniramine maleate; buspirone; caffeine; calamine calcium, calcium carbonate, casinate and hydroxide camphor; captopril; cascara sagrada; castor oil cefaclor; ce
  • CCK-B antagonists are CCK-B antagonists. These compounds are described in copending U.S. Serial Numbers 629,809 filed 12/19/90, 576,308 filed 8/31/90, 576,628 filed 8/31/90, 576,296 filed 8/31/90, 576,315 filed 8/31/90, 576,024 filed 8/31/90 and 576,297 filed 8/31/90, all of which are herein incorporated by reference.
  • One especially useful compound is tR-(R*,R*) ]-4-[ [2-[ [3-(lH-indol-3-Yl)-2-methyl-l-oxo-2-[- [(tricyclo [3.3.1.1 3' 7] dec-2-yloxy)- carbonyl] amino] propyll- amino]-1- phenylethyl]- amino]-4- oxobutanoic acid.
  • inventive compositions can be used in conjunction with ion exchange resins, cosmetic preparations, comestibles such as gum and confectionery products, as well as food products.
  • the controlled release compositions of the instant invention may be used to produce aerated confectioneries such as ropes, rolls, films, chewable candies, hard candies, puffed snacks as well as aerated chewing gums.
  • the aeration techniques used may be produced by foaming techniques.
  • the inventive compositions can also be used in encapsulation applications for flavors, sweeteners, spices and other ingredients used in the food art.
  • Our particularly novel usage relates to the formation of potato chips and other fried starch-based foods using extrusion or injection molding techniques, thereby creating a healthier product.
  • Bioadhesive formulations for use in snacks, mints and chewing gum are also contemplated.
  • inventive compositions may be formed into dry or liquid soup formulations. Cereals may also be blended or coated with the inventive compositions. Co-extruded products are also possible.
  • inventive compositions can also be used in a variety of food formulas to modify the texture and plasticization as well as to produce better compatibility with other ingredients.
  • the inventive compositions may be employed to extend the flavor and/or sweetness of the gum.
  • the inventive simmer compositions may be used in amounts of up to about 85% by weight of the final chewing gum composition. Preferred amounts are about 15 to about 70% by weight and most preferably about 20 to about 50% by weight.
  • the gum base may be any water-insoluble gum base well known in the art. Illustrative examples of suitable polymers in gum bases include both natural and synthetic elastomers and rubbers. The inventive compositions, however, may lend theirself to formulating biodegradable gum bases per se.
  • Gum base compositions may contain elastomer solvents to aid in softening the rubber component.
  • elastomer solvents may comprise any of the conventional solvents- such as wood rosins and terpene resins.
  • the solvent may be employed in an amount ranging from about 10% to about ⁇ % ano _ preferably about 45% to about 70% by weight of the gum base.
  • the chewing gum composition may include the conventional additives of flavoring agents, coloring agents, plasticizing agents, softeners and other ingredients. Preferably, these ingredients may be used in amounts of about 10% to about 30% by weight of the final chewing gum.
  • sweeteners are useful including sucrose, amino acid-based sweeteners, chloro derivatives of sucrose, dihydroflavinol, hydroxyguaiacol esters, L-amino dicarboxylic acid gem-diamines, L-aminodicarboxylic acid, aminoalkenoic acid ester amides, dipeptide sweeteners, glycyrrhizin, saccharin and its salts, acesulfame salts, cyclamates, steviosides, talin, dihydrochalcone compounds and mixtures thereof.
  • the sweeteners which may be released from the matrix may be used in amounts necessary to impart sweetness and preferably in amounts of about 1% to about 30% by weight of the matrix.
  • Aspartame, saccharin, sucralose, acesulfame and its salts are the preferred sweeteners and may be used in amounts of about 1% to about 50% and about 1% to 50%, respectively, by weight of the matrix.
  • the preferred amounts of these sweeteners are about 2 to about 25%, most preferably about 5 to about 15%.
  • Suitable flavorings including both natural and artificial flavors, and mints such as peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, and the like are contemplated.
  • the flavorings are generally utilized in amounts that will vary depending upon the individual flavor and may, for example, range in amounts of about 0.5% to about 3% by weight of the final chewing gum composition.
  • additives can be incorporated into the inventive compositions for their intended functions.
  • classes of additives include excipients, lubricants, buffering agents, disintegrating agents, stabilizers, foaming agents, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, antiadherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof.
  • These additives may be added before heating the starch to form the melt or after this step.
  • Useful additives include, for example, gelatin, vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, rape seed proteins, blood proteins, egg proteins, acrylated proteins; water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanth), pectin; water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and - hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxpropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as: cellulose acetate phthalate (CAP), Hydroxypropylmethylcellulose (HPMCP); carboxyalkylcelluloses, carboxyalkylalkylcelluloses
  • Such extenders may optionally be added in any desired amount preferably within the range of up to about 80%, preferably about 3 to 50% and more preferably within the range of 3% to 20% based on the weight of all components.
  • additives may be inorganic fillers, such as the oxides of magnesium, aluminum, silicon, titanium, etc. preferably in a concentration range of about 0.02 to about 3% by weight and preferably about 0.02 to about 1% based on the weight of all components.
  • plasticizers which include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene .
  • glycols organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate; propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, added in concentrations ranging
  • coloring agents include known azo dyes, i * organic or inorganic pigments, or coloring agents of natural origin.
  • Inorganic pigments are preferred, such as the oxides or iron or titanium, these oxides, being added in concentrations ranging from about 0.001 to about 10%, and preferably about 0.5 to about 3%, based on the 0 weight of all the components.
  • the starch material may further be added compounds to improve the flow properties of the starch material such as animal or vegetable fats, preferably in their hydrogenated form, 5 especially those which are solid at room temperature.
  • animal or vegetable fats preferably in their hydrogenated form, 5 especially those which are solid at room temperature.
  • These fats preferably have a melting point of 50°C or higher.
  • Preferred are triglycerides with C 12 ⁇ , C 14 -, C, ⁇ -, C 1R -, C ?0 - and C_ favor- fatty acids.
  • These fats can be added alone without adding extenders or plasticizers and 0 can be advantaegously added alone or together with mono- and/or diglycerides or phosphatides, especially lecithin.
  • the mono- and diglycerides are preferably derived from the types of fats described above, i.e. with C*. ⁇ - , C_..-, C- 6 -, C.g-, C, 0
  • the total amounts used of the fats, mono-, diglycerides and/or lecithins are up to about 5% and preferably within the range of about 0.5 to about 2% by weight of the total composition. It is further useful to add silicon dioxide or titanium dioxide in a concentration of about 0.02 to about 1% by weight of the total composition. These - compounds act as texturizing agents.
  • Excipients may generally include croscarmellose sodium, pregelatinized starch, sodium starch glycolate, unmodified starch and crospovidone. These excipients are
  • carbonate salts include, but are not
  • excipient 15 limited to, sodium carbonate, sodium bicarbonate, calcium carbonate and magnesium carbonate.
  • excipients may be combined with the active ingredient in any form, e.g., " by compression, molding or pelletizing.
  • the preferred excipient for rapid release is sodium carbonate.
  • additives are to be used in amounts sufficient to achieve their intended purpose. Generally, the 5 combination of certain of these additives will alter the overall release profile of the active ingredient and can be used to modify, i.e. impede or accelerate the release.
  • Useful dosage forms include without limitation oral 0 forms such as tablets, capsules, beads, granules, aggregates, syrups, powders, gels, solids, semi-solids, suspensions and liquids.
  • Injectable forms, lotions, transdermal delivery systems including patches, implantable forms or devices, aerosols or nasal mists, * suppositories, salves and ointments are also useful.
  • a capsule may be comprised of and/or contain the inventive
  • the capsule may
  • the actives in the capsule walls may be the same as or different from those inside the capsule cavity.
  • Injection molding may be used to form capsules, tablets and other shapes such as suppositories, dipsticks and implantable devices.
  • Filming thermoforming, blow molding, extrusion, coextrusion and other known thermoplastic processing techniques can be 0 employed. Cast molding into sheets and bars are also effective fabrication techniques.
  • the pellets were then cryogenically milled into a powder to facilitate compression into a tablet. Due to the high hygroscopicity of the MDS, milling to fine uniform particulates is difficult, as the material is 5 usually soft and rubbery, depending on the water content. Freezing the pellets prior to milling with liquid nitrogen or dry ice first allows for uniform communition. Subsequent to communition, the liquid nitrogen or dry ice are evaporated under controlled conditions to retain moisture in the sample.
  • the particle mesh size has not been found to be critical and will vary depending on the particular application and/or starch employed. Generally, for pharmaceutical applications, U.S. mesh sizes of about 20 to about 100 are used, corresponding to micron size ranges of about 850 to about 150 respectively.
  • the milled MDS composition was then intimately dry mixed with each of the following compositions containing the highly water-soluble drug tacrine hydrochloride
  • Example 3 (conventional) is identical in components to Example 2 (inventive) except that instead of using MDS as the matrix, ordinary commercially available native starch is used. This demonstrates the SR effect MDS has on the drug composition.
  • Dissolution studies are conducted using three different media recommended by USP for evaluating oral solid dosage forms: Distilled water; O.IN hydrochloric acid; and 0.05M pH 7.5 phosphate buffer. As graphically shown in Figure 2, the SR profile over 24 hours is nearly . identical irrespective of the media.
  • This example employs native, commercially available potato starch "as is” without further processing, as the formulation matrix.
  • This composition is similar to
  • Example 3 except it does not have the other additives contained in CSM.
  • This example substitutes glyceryl behenate NF lubricant in place of magnesium stearate of Example 5.
  • one parameter which is known to affect release properties of a drug composition is the relative proportion of drug to matrix.
  • the higher the drugrmatrix ratio the less sustained release due to the smaller proportion of matrix available to erode and thereby control diffusion and release of the drug.
  • the purpose of this example is to obtain a relatively fast release composition.
  • the MDS composition of Table 1 was used in this example as the matrix for a drug composition for the highly water-insoluble drug, gemfibrozil. This composition was incorporated in a dry mixed form into a standard, commercially available gelatin capsule (No. 0 capsule).
  • Figure 7 shows the dissolution release over 60 minutes indicating a relatively fast release.
  • Figure 8 illustrates the immediate release profile of capsules containing this composition.
  • MDS molecularly dispersed starch
  • shear, temperature and water content all of which occur in a closed volume. These parameters can be adjusted within the ranges of for example, about 80°C to about 240°C and preferably about 110°C to about 170°C; about 5% to about 45% water and with sufficient shear (screw speed, screw geometry and barrel length) for a time long enough to destructurize or substantially destroy the granular structure of the starch.
  • the choice of these parameters can product different "levels” or "degrees” of destructurization.
  • the different degrees of destructurization can be measured by various methods.
  • One such method for example, is to measure the remaining amount of granular structure contained in the destructurized starch. This can be determined by known microscopic methods.
  • Gelatinized starch on the other hand, is often cooked at various temperatures ranging from 55°C to 75°C and may be agitated or mixed using conventional mixing equipment. The resultant product, however cannot be said to be a melt or to be in the destructurized or molecularly dispersed form. This can be determined under standard optical microscopy - techniques.
  • Tablets (300 mg) comprising a matrix of 287.2 mg of starch which has been subjected to various processing temperatures and shear during extrusion were fabricated
  • This example uses the pancreatin USP to simulate intestinal fluid and demonstrates the effect of this enzyme on MDS matrices.
  • MDS was prepared at 160°C and 5 300 mg tablets were compressed comprising 287.2 mg MDS and 12.8 mg of tacrine HCI. The tablets were then subjected to dissolution media having a pH of 7.5 and containing 10 g/L pancreatin. Identical test tablets were also run in standard HCI media (pH 1.2) as a 0 comparison. The results, shown in Figure 11, demonstrate that the sustained release action of MDS matrices is reduced but still effective in simulated intestinal fluid. Further sustained release can be obtained through various additives which slow the * degradation of the starch by pancreatin.
  • the MDS composition in Table 1 is duplicated using wheat starch and corn starch in place of potato starch. The MDS composition is then combined with the following water-soluble therapeutic agents in the amounts as shown.
  • This example demonstrates the effect of the matrix to drug ratio upon the release profile over a 24 hour 5 period.
  • the following components are formulated using MDS and water-soluble drugs.
  • a water-soluble suppository dosage form having the « following composition is made:
  • the components are mixed in a heated jacketed bottle 0 and transferred to molds to cool.
  • Example 13 The granulations of Example 13 are coated with one 5 of the following encapsulating materials selected from ethylcellulose, methylmethacrylate copolymers, and cellulose acetate. The granulations are then incorporated both in tablets and capsules.
  • composition is prepared in the form of an injection molded or foamed suppository for vaginal application: 5
  • the components are combined in an extruder or injection molding machine. If an extruder is used, a foamed product is produced. The foamed product is . designed for immediate release.
  • composition is prepared as a suspension:
  • composition is prepared in the form of a suppository designed to release the therapeutic active via melting.
  • composition is prepared in the form of an ointment.
  • composition was mixed in a jacketed kettle at 80-90°C and allowed to cool to form the ointment.
  • a formulation comprising destructurized starch and an excipient to promote erosion and a control formulation were prepared as follows:
  • Formulations were prepared having the following compositions: (mg/tablet)
  • the formulations were prepared by mixing Cab-O-Sil with the active ingredient in a suitable blender. Destructurized starch that had been screened through No. 30 screen mesh to remove aggregates, or a comparison ' starch, as appropriate, was then added and the components were then blended for 15 minutes in a high shear mixer. Finally, the lubricant was added, and the entire mixture was blended for 3 minutes without using an intensifier bar.
  • the release profiles of the formulations are shown in Figure 18.
  • the formulations were prepared by mixing Cab-O-Sil with the active ingredient in a suitable blender.
  • the formulations were prepared by mixing Cab-O-Sil with the active ingredient in a suitable blender. Destructurized starch that had been screened through No. 30 screen mesh to remove aggregates, or a comparison starch, as appropriate, was then added and the components were then blended for 15 minutes in a high shear mixer. Finally, the lubricant was added, and the entire mixture was blended for 3 minutes without using an intensifier bar, although 900 ml of distilled water was used to aid in mixing. The release profiles of the formulations are shown in Figure 20. EXAMPLE 30
  • the formulations were prepared using the standard USP method using 2 paddles at 100 rpm at 37 degrees C.
  • the formulations were tested both in environments containing pH buffer of 7.5 and in buffered solutions (pH 7.5) containing intestinal enzymes, including amylases.
  • the release profiles of the formulations are shown in Figures 21 and 22.
  • the formulations were prepared using the standard USP method using 2 paddles at 100 rpm at 37 degrees C.
  • the formulations were tested in an environment containing pH buffer of 7.5.
  • the release profiles of the formulations are shown in Figure 25.
  • Formulations were prepared having the following compositions: (mg/tablet)
  • the formulations were prepared using the standard USP method using 2 paddles at 100 rpm at 37 degrees C.
  • the formulations were tested both in environments containing pH buffer of 7.5 and in buffered solutions (pH 7.5) containing intestinal enzymes, including amylases.-
  • the release profiles of the formulations are shown in Figures 26 and 27.

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Abstract

L'invention se rapporte à des compositions à libération régulée comprenant: (i) une matrice contenant de l'amidon ayant été traité sous l'action d'une force de cisaillement à des températures comprises entre environ 80 °C et environ 240 °C dans un volume fermé, la teneur en eau de la matrice étant maintenue à un pourcentage en poids compris entre environ 5 et environ 45, calculé sur la base du mélange amidon/eau; et (ii) un ingrédient actif, tel que de préférence un ingrédient pharmaceutiquement actif, avec lequel la matrice est en contact intime, la matrice et l'ingrédient pharmaceutiquement actif étant présents en quantités suffisantes pour permettre la régulation de la libération de l'ingrédient pharmaceutiquement actif selon un dosage efficace.
PCT/US1992/001762 1991-03-01 1992-03-02 Compositions a liberation regulee a base d'amidon WO1992015285A1 (fr)

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564700A1 (fr) * 1992-04-10 1993-10-13 American Maize-Products Company Comprime pharmaceutique contenant de l'amidon blanc
WO1995003052A1 (fr) * 1993-07-22 1995-02-02 Warner-Lambert Company Systemes d'administration de medicament a base de tacrine a liberation controlee et procedes de preparation desdits systemes
WO1996000065A1 (fr) * 1994-06-27 1996-01-04 Alza Corporation Compositions pharmaceutiques a base de tacrine
WO1996009070A1 (fr) * 1994-09-21 1996-03-28 Wijdeven Gijsbertus Gerardus P Utilisation de l'amidon dans des applications transdermiques
US5565407A (en) * 1993-12-27 1996-10-15 University Of Kansas Center For Research, Inc. Biologically active agent encapsulated in biodegradable starch/polymer matrices
FR2747306A1 (fr) * 1996-04-15 1997-10-17 Oreal Utilisation d'un polymere hydrocarbone pour la fixation et/ou la liberation prolongee de parfum
EP0711506A3 (fr) * 1994-10-14 1999-10-27 Rijksuniversiteit te Groningen Gomme à mâcher
EP0992251A1 (fr) * 1998-10-07 2000-04-12 Isotis B.V. Dispositif pour la régénération osseuse d'un équivalent osseux
WO2000050014A2 (fr) * 1999-02-23 2000-08-31 Mylan Pharmaceuticals, Inc. Compositions pharmaceutiques a base de phenytoine sodique
WO2000064415A1 (fr) * 1999-04-22 2000-11-02 Euroceltique S.A. Procede de realisation d'une matrice a action prolongee amorphe ou partiellement amorphe insoluble dans l'eau
WO2004054550A1 (fr) * 2002-12-16 2004-07-01 Ranbaxy Laboratories Limited Compositions pharmaceutiques de phenytoine sodique a liberation prolongee
WO2005115343A2 (fr) 2004-05-28 2005-12-08 Abbott Gmbh & Co. Kg Forme galénique obtenue à partir d'un mélange pulvérulent contenant un pigment inorganique
US20060233873A1 (en) * 2003-01-24 2006-10-19 Julien Meissonnier Dispersion of taste masked crystals or granules of active substances, chewable soft capsules filled with said dispersion, and process for preparing same
WO2008105663A1 (fr) * 2007-03-01 2008-09-04 Bioneedle Technologies Group B.V. Implant contenant de l'amidon déstructuré
US20090269401A1 (en) * 2005-11-11 2009-10-29 Masaaki Endo Controlled Release Solid Preparation
US20090274767A1 (en) * 2006-11-24 2009-11-05 Bayer Cropscience Ag Plant protection granulates to be applied to leaf surface
WO2014159609A1 (fr) * 2013-03-14 2014-10-02 Allergen Research Corporation Préparations à base d'arachide et leurs utilisations
CN105012265A (zh) * 2015-08-19 2015-11-04 上海华源安徽锦辉制药有限公司 一种含有苯妥英钠化合物的药物组合物及其制备方法
RU2629595C1 (ru) * 2016-09-08 2017-08-30 федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский государственный медицинский университет имени В.И. Разумовского" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Саратовский ГМУ им. В.И. Разумовского Минздрава России) Препарат для регенерации мягких тканей с антибактериальным эффектом
RU2629596C1 (ru) * 2016-09-08 2017-08-30 федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский государственный медицинский университет имени В.И. Разумовского" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Саратовский ГМУ им. В.И. Разумовского Минздрава России) Порошкообразный препарат с антибактериальным и регенерирующим эффектами
US10449118B2 (en) 2013-03-14 2019-10-22 Aimmune Therapeutics, Inc. Manufacture of peanut formulations for oral desensitization
US11229673B2 (en) 2019-05-10 2022-01-25 Société des Produits Nestlé S.A. Methods for improving the quality of life of a patient with a peanut allergy

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EP0118240A2 (fr) * 1983-02-18 1984-09-12 Warner-Lambert Company Procédure pour moulage par injection d'amidon
WO1990005161A1 (fr) * 1988-11-03 1990-05-17 Ivan Tomka Amidon pouvant etre mis en ×uvre a l'etat thermoplastique et procede de fabrication correspondant

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EP0118240A2 (fr) * 1983-02-18 1984-09-12 Warner-Lambert Company Procédure pour moulage par injection d'amidon
WO1990005161A1 (fr) * 1988-11-03 1990-05-17 Ivan Tomka Amidon pouvant etre mis en ×uvre a l'etat thermoplastique et procede de fabrication correspondant

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STN Information Services Data Base: Chemical Abstracts, vol. 112, no. 4, (Columbus, Ohio, US), J. HERMAN et al.: "Modified starches as hydrophilic matrixes for controlled oral delivery. I. Production and characterization of thermally modified starches", see abstract no. 25512n, & INT. J. PHARM., 1989, 56(1), 51-63, see the whole abstract (cited in the application) *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5292519A (en) * 1992-04-10 1994-03-08 American Maize Technology, Inc. Process for producing a pharmaceutical tablet using a homozygous white starch
EP0564700A1 (fr) * 1992-04-10 1993-10-13 American Maize-Products Company Comprime pharmaceutique contenant de l'amidon blanc
WO1995003052A1 (fr) * 1993-07-22 1995-02-02 Warner-Lambert Company Systemes d'administration de medicament a base de tacrine a liberation controlee et procedes de preparation desdits systemes
US5576022A (en) * 1993-07-22 1996-11-19 Warner Lambert Company Controlled release tacrine drug delivery systems and methods for preparing same
US5565407A (en) * 1993-12-27 1996-10-15 University Of Kansas Center For Research, Inc. Biologically active agent encapsulated in biodegradable starch/polymer matrices
US5698224A (en) * 1994-06-27 1997-12-16 Alza Corporation Tacrine therapy
WO1996000065A1 (fr) * 1994-06-27 1996-01-04 Alza Corporation Compositions pharmaceutiques a base de tacrine
US6036973A (en) * 1994-06-27 2000-03-14 Alza Corporation Therapy for neurological diseases
US6001385A (en) * 1994-09-21 1999-12-14 Van De Wijdeven; Giisbertus G. P. Use of starch for transdermal applications
AU711798B2 (en) * 1994-09-21 1999-10-21 Injectile Technologies Gmbh Use of starch for transdermal applications
WO1996009070A1 (fr) * 1994-09-21 1996-03-28 Wijdeven Gijsbertus Gerardus P Utilisation de l'amidon dans des applications transdermiques
NL9401534A (nl) * 1994-09-21 1996-05-01 Gijsbertus Gerardus Petrus Van Gebruik van zetmeel voor parenterale toepassingen.
EP1250936A1 (fr) * 1994-09-21 2002-10-23 Injectile Technologies GmbH Utilisation de l' amidon dans des applications transdermiques
EP0711506A3 (fr) * 1994-10-14 1999-10-27 Rijksuniversiteit te Groningen Gomme à mâcher
FR2747306A1 (fr) * 1996-04-15 1997-10-17 Oreal Utilisation d'un polymere hydrocarbone pour la fixation et/ou la liberation prolongee de parfum
EP0992251A1 (fr) * 1998-10-07 2000-04-12 Isotis B.V. Dispositif pour la régénération osseuse d'un équivalent osseux
WO2000050014A3 (fr) * 1999-02-23 2000-12-21 Mylan Pharmaceuticals Inc Compositions pharmaceutiques a base de phenytoine sodique
US6274168B1 (en) 1999-02-23 2001-08-14 Mylan Pharmaceuticals Inc. Phenytoin sodium pharmaceutical compositions
WO2000050014A2 (fr) * 1999-02-23 2000-08-31 Mylan Pharmaceuticals, Inc. Compositions pharmaceutiques a base de phenytoine sodique
US6620432B2 (en) 1999-02-23 2003-09-16 Mylan Pharmaceuticals Inc. Phenytoin sodium pharmaceutical compositions
WO2000064415A1 (fr) * 1999-04-22 2000-11-02 Euroceltique S.A. Procede de realisation d'une matrice a action prolongee amorphe ou partiellement amorphe insoluble dans l'eau
AU763609B2 (en) * 1999-04-22 2003-07-31 Euro-Celtique S.A. Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix
EP1839651A1 (fr) * 1999-04-22 2007-10-03 Euro-Celtique S.A. Procédé de réalisation d'une matrice à action prolongée amorphe insoluble dans l'eau
KR100511113B1 (ko) * 1999-04-22 2005-08-31 유로-셀띠끄 소시에떼 아노님 비수용성 비정질 또는 부분비정질 서방성 매트릭스의 제조방법
US8557286B1 (en) * 1999-04-22 2013-10-15 Euroceltique, S.A. Method for producing a water-insoluble amorphous or partially amorphous controlled release matrix
WO2004054550A1 (fr) * 2002-12-16 2004-07-01 Ranbaxy Laboratories Limited Compositions pharmaceutiques de phenytoine sodique a liberation prolongee
US20060233873A1 (en) * 2003-01-24 2006-10-19 Julien Meissonnier Dispersion of taste masked crystals or granules of active substances, chewable soft capsules filled with said dispersion, and process for preparing same
WO2005115343A2 (fr) 2004-05-28 2005-12-08 Abbott Gmbh & Co. Kg Forme galénique obtenue à partir d'un mélange pulvérulent contenant un pigment inorganique
US9029427B2 (en) 2005-11-11 2015-05-12 Asahi Kasei Chemicals Corporation Controlled release solid preparation
US20090269401A1 (en) * 2005-11-11 2009-10-29 Masaaki Endo Controlled Release Solid Preparation
US20090274767A1 (en) * 2006-11-24 2009-11-05 Bayer Cropscience Ag Plant protection granulates to be applied to leaf surface
US8323697B2 (en) * 2006-11-24 2012-12-04 Bayer Intellectual Property Gmbh Plant protection granulates to be applied to leaf surface
WO2008105663A1 (fr) * 2007-03-01 2008-09-04 Bioneedle Technologies Group B.V. Implant contenant de l'amidon déstructuré
US8486439B2 (en) 2007-03-01 2013-07-16 Bioneedle Technologies Group B.V. Parenteral formulation
US9492535B2 (en) 2013-03-14 2016-11-15 Aimmune Therapeutics, Inc. Peanut formulations and uses thereof
WO2014159609A1 (fr) * 2013-03-14 2014-10-02 Allergen Research Corporation Préparations à base d'arachide et leurs utilisations
US10086068B2 (en) 2013-03-14 2018-10-02 Aimmune Therapeutics, Inc. Peanut formulations and uses thereof
US10449118B2 (en) 2013-03-14 2019-10-22 Aimmune Therapeutics, Inc. Manufacture of peanut formulations for oral desensitization
US10512686B2 (en) 2013-03-14 2019-12-24 Aimmune Therapeutics, Inc. Peanut formulations and used thereof
US10653773B2 (en) 2013-03-14 2020-05-19 Aimmune Therapeutics, Inc. Peanut formulations and uses thereof
US11141352B2 (en) 2013-03-14 2021-10-12 Société des Produit Nestlé S.A. Manufacture of peanut formulations for oral desensitization
US12016917B2 (en) 2013-03-14 2024-06-25 Société des Produits Nestlé S.A. Peanut formulations and uses thereof
CN105012265A (zh) * 2015-08-19 2015-11-04 上海华源安徽锦辉制药有限公司 一种含有苯妥英钠化合物的药物组合物及其制备方法
RU2629595C1 (ru) * 2016-09-08 2017-08-30 федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский государственный медицинский университет имени В.И. Разумовского" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Саратовский ГМУ им. В.И. Разумовского Минздрава России) Препарат для регенерации мягких тканей с антибактериальным эффектом
RU2629596C1 (ru) * 2016-09-08 2017-08-30 федеральное государственное бюджетное образовательное учреждение высшего образования "Саратовский государственный медицинский университет имени В.И. Разумовского" Министерства здравоохранения Российской Федерации (ФГБОУ ВО Саратовский ГМУ им. В.И. Разумовского Минздрава России) Порошкообразный препарат с антибактериальным и регенерирующим эффектами
US11229673B2 (en) 2019-05-10 2022-01-25 Société des Produits Nestlé S.A. Methods for improving the quality of life of a patient with a peanut allergy

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