CA2065210C - Controlled release matrix for pharmaceuticals - Google Patents

Controlled release matrix for pharmaceuticals Download PDF

Info

Publication number
CA2065210C
CA2065210C CA 2065210 CA2065210A CA2065210C CA 2065210 C CA2065210 C CA 2065210C CA 2065210 CA2065210 CA 2065210 CA 2065210 A CA2065210 A CA 2065210A CA 2065210 C CA2065210 C CA 2065210C
Authority
CA
Canada
Prior art keywords
composition
sodium alginate
controlled release
active agent
calcium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA 2065210
Other languages
French (fr)
Other versions
CA2065210A1 (en
Inventor
Thinnayam N. Krishnamurthy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euroceltique SA
Original Assignee
Euroceltique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US758,883 priority Critical
Priority to US07/758,883 priority patent/US5215758A/en
Application filed by Euroceltique SA filed Critical Euroceltique SA
Publication of CA2065210A1 publication Critical patent/CA2065210A1/en
Application granted granted Critical
Publication of CA2065210C publication Critical patent/CA2065210C/en
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/02Suppositories; Bougies; Bases therefor; Ovules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1611Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S424/00Drug, bio-affecting and body treating compositions
    • Y10S424/15Suppositories
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/964Sustained or differential release type
    • Y10S514/965Discrete particles in supporting matrix
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S514/00Drug, bio-affecting and body treating compositions
    • Y10S514/966Rectal

Abstract

The controlled release of therapeutically active agents is achieved from a controlled release matrix of sodium alginate and a calcium salt. When the composition is to be administered rectally, the matrix is combined with a therapeutically active agent and a suitable suppository base. When the composition is to be administered orally, the matrix further includes a higher aliphatic alcohol.

Description

~as~mo CONTROLLED RELEASE MATRIX
FOR PHARMACEUTICALS
Sustained release dosage forms are central in the search for improved therapy, both through improved patient compliance and decreased incidences of adverse drug reactions. Ideally, a controlled release dosage form will provide therapeutic concentration of the drug in blood that is maintained throughout the dosing interval with a reduction in the peak/nadir concentration ratio. Central to the development process are the many variables that influence the in-vivo release and subsequent absorption of the active ingredients from the gastrointestinal tract.
Controlled release formulations known in the art include specially coated beads or pellets, coated tablets and ion exchange resins, wherein the slow release of the active drug is brought about through selective breakdown of the coating of the preparation or through formulation with a special matrix to affect the release of the drug. Some controlled release formulations provide for sequential release of a single dose of an active medicament at predetermined periods after administration.
It is the aim of all controlled release preparations to provide a longer duration of pharmacological response after the administration of the dosage form than is ordinarily experienced after the administration of an immediate release dosage form.
Such extended periods of response provides for many inherent therapeutic benefits that are not achieved with short acting, immediate release products. Thus, therapy may be continued without interrupting the sleep of the patient, which is of ~ecial importance when treating an epileptic patient to prevent nocturnal seizures, or patients with pain who experience severe pain on awakening, as well as for debilitated patients for whom an uninterrupted sleep is essential.
Another critical role for extending the duration of action of medications is in therapy of cardiovascular diseases wherein optimal peak blood levels of a medication must be maintained at steady state level in order to achieve the desired therapeutic effect. Unless conventional immediate release dosage forms are carefully administered at frequent intervals, peaks and valleys in the blood level of the active drug occur because of the rapid absorption and systemic excretion of the compound and through metabolic inactivation, thereby producing special problems in maintenance therapy of the patient. A further general advantage of longer acting drug preparations is improved patient compliance resulting from the avoidance of missed doses through forgetfulness.
The prior art teaching of the preparation and use of compositions providing for controlled release of an active compound from a carrier is basically concerned with the release of the active substance into the physiologic fluid of the alimentary tract. However, it is generally recognized that the mere presence of an active substance in the gastrointestinal fluids does not, by itself, insure bioavailability.
Bioavailability, in a more meaningful sense, is the degree, or amount, to which a drug substance is absorbed into the systemic circulation in order to be available to a target tissue site.
To be absorbed, an active drug substance must be in solution. The time required for a given proportion of an active drug substance contained in a dosage unit to enter into solution in appropriate physiologic fluids is known as the dissolution time. The dissolution time of an active substance from a dosage 'nit is determined as the proportion of the amount of active drug substance released from the dosage unit over a specified time by a test method conducted under standardized conditions. The physiologic fluids of the gastrointestinal tract are the media for determining dissolution time. The present state of the art recognizes many satisfactory test procedures to measure dissolution time for pharmaceutical compositions, and these test procedures are described in official compendia world wide.
Although there are many diverse factors which influence the dissolution of a drug substance from its carrier, the dissolution time determined for a pharmacologically active substance from a specific composition is relatively constant and reproducible.
Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Thus, the dissolution concentration of an active drug substance is dynamically modified in this steady state as components are removed from the dissolution medium through absorption across the tissue site.
Under physiological conditions, the saturation level of the dissolved materials is replenished from the dosage form reserve to maintain a relatively uniform and constant dissolution concentration in the solvent medium, providing for a steady state absorption.
The transport across a tissue absorption site in the gastrointestinal tract is influenced by the Donnan osmotic equilibrium forces on both sides of the membrane, since the direction of the driving force is the difference between the concentrations of active substance on either side of the membrane, i.e. the amount dissolved in the gastrointestinal ~uids and the amount present in the blood. Since the blood levels are constantly being modified by dilution, circulatory changes, tissue storage, metabolic conversion and systemic excretion, the flow of active materials is directed from the gastrointestinal tract into the blood stream.
Notwithstanding the diverse factors influencing both dissolution and absorption of a drug substance. A strong correlation has been established between the in-vitro dissolution time determined for a dosage form and the in-vivo bioavailability. this correlation is so firmly established in the art that dissolution time has become generally descriptive of bioavailability potential for the active component of the particular dosage unit composition. In view of this relationship, it is clear that the dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating controlled release compositions.
Certain controlled release pharmaceutical compositions for oral administration consisting of a release matrix of sodium alginate and calcium salts have been discussed in the art. For example, in vitro evaluations of floating alginate gel-systems consisting of sodium alginate, calcium phosphate, sodium bicarbonate, drug and diluent filled in a gelatin capsule have been reported by Protan. Protan also reports that a method for treatment of diabetes by encapsulating islets of Langerhans in calcium alginate beads coated with a semi-permeable membrane have been developed.
However, less attention has been paid to the production of formulations where the route of administration is other than oral or where the active drug is highly water soluble. In situations where a drug cannot be taken orally, or where the physical condition does not permit oral administration, an alternate route ~0 652 10 _ of administration with a similar controlled release profile as the oral route is highly desirable.
In addition, improvements in the controlled release of therapeutically active agents from matrices of calcium salts/sodium alginates are also desirable.
SUMMARY OF THE INVENTION
One aspect of the present invention is to provide a new controlled release matrix which extends the time of release of active medicaments incorporated therein.
Another aspect of the present invention is to provide controlled release matrix compositions which are useful for all types of pharmaceutically active ingredients and which can extend the time of release o~ all such ingredients.
It is yet another aspect of the present invention to provide a controlled release matrix useful in rectal formulations.
In accordance with the above aspects and others, the present invention is directed to controlled release compositions for the controlled release of therapeutically active ingredients over a pre-determined period of time, e.g. from five hours to as much as 24 hours after administration in human or animals.
More particularly, the present invention is related to a controlled release pharmaceutical composition for rectal administration, comprising a controlled release matrix comprising a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium salt, a therapeutically active agent, and a suitable vehicle which melts or dissolves in rectal fluids. The calcium salt cross-links with the sodium alginate when the vehicle dissolves or melts, or when the components ore exposed to aqueous solutions. Thereby, the release of the therapeutically active agent from the composition is controlled.

The present invention is also related to a controlled release pharmaceutical composition for oral administration, comprising a controlled release matrix comprising a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt which cross-links with the sodium alginate when the composition is exposed to aqueous solutions, an effective amount of a higher aliphatic alcohol, and an effective amount of an active agent distributed or suspended in said controlled release matrix. The amount of higher aliphatic alcohol included is sufficient to obtain a desired rate of release of the active agent. The higher aliphatic alcohol preferably contains from about 8 to about 18 carbon atoms.
The present invention is further related to a controlled release matrix for the release of an orally administered therapeutically active agent, comprising from about 10 to about 50 percent by weight of a pharmaceutically acceptable sodium alginate, a sufficient amount of a pharmaceutically acceptable calcium salt to cross-link with the sodium alginate when the matrix is exposed to aqueous solutions or gastric fluid, and an effective amount of a higher aliphatic alcohol to obtain a desired rate of release of an active agent to be incorporated into the matrix.
The present invention is also related to a method for providing a controlled release suppository containing a pharmaceutically active agent, comprising combining a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt in an amount effective to cross-link with the sodium alginate, and an effective amount of a therapeutically active agent, and then adding the mixture to sufficient quantity of a suitable melted vehicle. Suppositories are then prepared by pouring the mixture into molds and cooling.

The present invention is further related to a method of providing a orally administered controlled release composition for a therapeutically active agent, comprising preparing a controlled release matrix by combining a pharmaceutically acceptable sodium alginate with a pharmaceutically acceptable calcium salt capable of cross-linking the sodium alginate when exposed to aqueous solutions, a higher aliphatic alcohol, and an effective amount of a therapeutically active agent, such that the therapeutically active agent is suspended or distributed in the matrix, and including a sufficient amount of the calcium salt and higher aliphatic alcohol to control the release of said therapeutically active agent from the matrix at a desired rate when the composition is exposed to aqueous solutions.
DETAILED DESCRIPTION
An important aspect of the present invention is related in part to the realization that a controlled release matrix for the oral administration of a wide variety of therapeutically active agents is obtained from the combination of a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt, and a higher aliphatic alcohol.
Another important aspect of the present invention is directed to the discovery that a controlled release composition for rectal administration of a wide variety of drugs can be obtained from the combination of a pharmaceutically acceptable I
sodium alginate, a pharmaceutically acceptable calcium salt.
The bioavailability of rectally administered drugs is known to be erratic, and it is commonly the case that rectal absorption of a drug may be substantially different from absorption following oral administration.

Among the different factors affecting the dissolution time are the surface area of the drug substance presented to the dissolution solvent medium, the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. In the case of an orally administered drug, the physiologic fluids of the gastrointestinal tract are the media for determining dissolution time. Generally, factors affecting the absorption of drugs from suppositories administered rectally include anorectal physiology, suppository vehicle, absorption site pH, drug pKe, degree of ionization, and lipid solubility.
Any pharmaceutically acceptable sodium alginate may be used in conjunction with the present invention the most preferred having a viscosity range between 10 - 500 cps as a one percent solution in water. More preferably, the alginate is a sodium alginate having a viscosity of from about 40 to about 150 cps as a one percent solution. In certain preferred embodiments the alginate has a viscosity from about 40 to about 70 cps as a one percent solution, for example when the matrix of the present invention is to be used in conjunction a less soluble drug or when a faster dissolution profile is desired. In other embodiments, the alginate has a viscosity from about 70 to about 150 cps, for example when the drug to be incorporated is relatively water soluble or when a slow dissolution rate is desired. In yet other preferred embodiments, the sodium alginate A
has a viscosity from about 300 to about 500 cps as a one percent solution.
In terms of particle size, the sodium alginate preferably has a particle size from about 45 to about 125 microns, more preferably has a particle size of 70 microns or less.

20 s52 ~o Any alginates which are pharmaceutically acceptable can be used for the purposes of the present invention. Examples of commercially available alginates suitable for use in conjunction with the present invention are those that are marketed under the trade-marks "Protanal*" and "Keltone*", and are available from Protan A/S, Norway and Merck & Co. Inc., New Jersey, U.S.A.
respectively.
The amount of alginate contained in the controlled release matrices and compositions of the present invention is dependent upon many factors, including the desired duration of action and the nature of the active drug substance to be incorporated into the composition. In general, the amount of alginate in the total composition is from about 10 to about 50 percent by weight and in certain embodiments more preferably from about 15 to about 30 percent by weight. The amount of alginate may be higher or lower depending upon the dosage regimen desired (once-a-day, twice-a-day, three times a day, etc.).
Suitable calcium salts for use in the matrices and compositions of the present invention include calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate, and calcium gluconate. other pharmaceutically acceptable calcium salts known in the art may also be used.
The amount of calcium salt in the compositions of the present invention must be sufficient to cross-link with the alginate when exposed to solutions (e.g. gastric fluid in the case of oral preparations, the melted base and rectal fluids in the case of a rectal preparation) such that a gel matrix is formed from which the drug is slowly released. Generally, in terms of the amount of sodium alginate in the composition, the amount of calcium salt is from about 2 to about 12 percent, and more preferably from about 8 to about 12 percent, by weight of the amount of sodium alginate present in the composition. In terms of the composition, the amount of calcium is generally from about 1 to about 4 percent, by weight.
Although it is preferred that calcium salts be used in the present invention, salts of other multivalent ions may be used instead such as Al3r.
Generally, the controlled release compositions of the present invention provide sustained release of the drugs) over a predetermined or a specified period of time, e.g. over a period of time from about 4-5 hours to as much as 24 hours after administration in humans or animals.
The controlled release compositions of the present invention for oral administration comprise a sodium alginate, a calcium salt and a higher aliphatic alcohol containing from 8 to 18 carbon atoms, which is optionally substituted by a further aliphatic group containing from about 8 to about 18 carbon atoms.
The controlled release compositions of the present invention may be administered orally in the form of tablets, capsules, etc. It is also contemplated that the compositions of the present invention may be adapted for buccal administration.
Examples of suitable higher aliphatic alcohols include fatty alcohols such as lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetostearyl alcohol, and mixtures thereof.
The level of higher aliphatic alcohol in the oral compositions of the present invention is determined by the rate of drug release required. Generally, the compositions will s contain from about 5% to about 45% (w/w), and preferably from about 10% to about 30% (w/w), of the higher aliphatic alcohol, as a proportion to the weight of the composition. The greater the amount of higher aliphatic alcohol included in the matrix, the slower the rate of release of the drug.

2065?10 Upon oral ingestion and contact with fluids, the compositions of the present invention swell and gel to form a matrix from which the drug is released. Since the drug is suspended or distributed throughout the composition (and consequently throughout the matrix), a constant amount of drug can be released per unit time in vivo by dispersion or erosion of the outer portions of the matrix.
Any pharmaceutically accepted soluble or insoluble inert pharmaceutical filler (diluent) material can be used in the compositions of the present invention, such as monosaccharides, disaccharides, polyhydric alcohols, or mixtures thereof. Examples of inert diluents include sucrose, dextrose, lactose, microcrystalline cellulose, xylitol, fructose, sorbitol, mixtures thereof and the like. However, it is preferred that a soluble pharmaceutical filler such as lactose, dextrose, sucrose, or mixtures thereof be used.
In the case of tablets, an effective amount of any generally accepted pharmaceutical lubricant, including the calcium or magnesium soaps may be added to the above-mentioned ingredients of the excipient be added at the time the medicament is added, or in any event prior to compression into a solid dosage form. Most preferred is magnesium stearate in an amount of about 0.5-3% by weight of the solid dosage form.
In preparing the matrices of the present invention for oral administration, the sodium alginate, calcium salt, drugs) and higher aliphatic alcohol can be combined together using a wet granulation technique of at least one step, to form a uniform granulate together with any of the other excipients that are required for the tableting or the capsule filling.
Alternatively, the drugs) can be combined during the process of preparing the granulate, or mixed with the granulate after it is prepared.

The moist granulated mass with or without the drugs) is then dried and then the granulate is sized using a suitable screening device, which then provides a flowable powder which can then be filled into capsules or compressed into matrix tablets or caplets.
The controlled release matrix for rectal administration comprises sodium alginate and a calcium salt. The composition for rectal administration further comprises a drug and a suitable suppository vehicle (base). The suppository base chosen should of course be compatible with the drugs) to be incorporated into the composition. Further, the suppository base is preferably nontoxic and nonirritating to mucous membranes, melts or dissolves in rectal fluids, and is stable during storage.
Prior to absorption, the drug must be in solution. In the case of suppositories, solution must be preceded by dissolution of the base, or the melting of the base and subsequent partition of the drug from the base into the rectal fluid.
The bioavailability of the drug can be altered by the suppository base. Thus, the particular base to be used in conjunction with a particular drug must be chosen giving consideration to the physical properties of the drug. For example, lipid-soluble drugs will not partition readily into the rectal fluid, but drugs that are only slightly soluble in the lipid base will partition readily into the rectal fluid.
In certain preferred embodiments of the present invention for both water-soluble and water-insoluble drugs, the suppository base comprises a fatty acid wax selected from the group consisting of mono-, di- and triglycerides of saturated, natural fatty acids of the chain length C~z to CAB.
In preparing the suppositories of the present invention other excipients may be used. For example, a wax may be used to ~~ 652 10 suspend the alginate and calcium salt, as well as to form the proper shape for administration via the rectal route.
This system can also be used without wax, but with the addition of diluent filled in a gelatin capsule for both rectal and oral administration.
Examples of suitable commercially available mono-, di- and triglycerides include saturated natural fatty acids of the 12-18 carbon atom chain sold under the trade-marks Novata* (types A.B, AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henkel and Witepsol" (types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55,~S58, E75, E76 and E85), manufactured by Dynamit Nobel.
Other pharmaceutically acceptable suppository bases may be substituted in whole or in part for the above-mentioned mono-, di- and triglycerides. The amount of base in the suppository is determined by the size (i.e. actual weight) of the dosage form, the amount of alginate and drug used. Generally, the amount of suppository base is from about 20 percent to about 90 percent by weight of the total weight of the suppository. Preferably, the amount of base in the suppository is from about 65 percent to about 80 percent, by weight of the total weight of the suppository.
In preparing the matrices of the present invention for rectal administration, the sodium alginate and calcium salt may be combined together with the drug. Thereafter, the suppository base can be melted, and the mixed powder added to the melted base and mixed. The uniform mixture is then poured into suppository shells, and the suppositories cooled.
The therapeutically active agents which may be used in the compositions of the present invention include a wide variety of drugs, including both water-soluble. and water-insoluble drugs.
Examples of different classes of therapeutically active f.....s ' ~p 652 10 .. pharmaceutical agents that can be incorporated into the matrices of the present invention include antihistamines (e. g., dimenhydrinate, diphenhydramine (50-100 mg), chlorpheniramine and dexchlorpheniramine maleate), analgesics (e. g., aspirinTM, codeine, morphine (15-300 mg), dihydromorphone, oxycodone, etc.), anti-inflammatory agents (e. g., naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, sulindac), gastro-intestinals and anti-emetics (e. g., metoclopramide (25-100 mg)), anti-epileptics (e. g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e. g., codeine phosphate), anti-asthmatics (e. g, theophylline), anti-spasmodics (e. g. atropine, scopolamine), hormones (e. g., insulin, leparin), diuretics (e. g., eltacrymic acid, bendrofluazide), anti-hypotensives (e. g., propranolol, clonidine), bronchodilators (e. g., albuterol), anti-inflammatory steroids (e. g., hydrocortisone, triamcinolone, prednisone), antibiotics (e. g., tetracycline), antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including apetite suppressants such as phenylpropanolamine). The above list is not meant to be exclusive.
DESCRIPTION OF PREFERRED EMBODTMENTS
The following examples are given to further illustrate the present invention. The scope of the invention is not, however, meant to be limited to the specific details of the examples.
.~.~MPLES 1-3 Morphine was tested in the controlled release system of the invention. The following three suppository formulations set forth in Table 1 denlonstr2~te the principle of the invention with ~ps52~o regard to.a controlled release morphine suppository containing 30 mg active ingredient, the applicability and the advantages for pharmaceutical use.

Mortihine Sugboai+r,.-y Form,~ati~T~
INGREDIENT
Z.
Morphine Sulphate .5H20 30.0 mg 30.0 mg 30.0 mg Sodium Alginate 327.5 mg 409.5 450.0 mg mg (low viscosity LF grade) DiCalcium phosphate 32.5 mg 40.5 mg 45.0 mg Novata-B 1410.0 1320 1275 ma 0 ma 0 . .
Total . 1800.0 1800.0 ma mg mg 1800.0 mg Novata-B'1'"' is a mixture of mono-, di- and triglycerides based on saturated natural fatty acids of the chain lengths C~Z to CAB, with a specific melting range (33.4'C - 25.5'C).
The suppositories were prepared according to the following method: morphine sulphate powder, sodium alginate and calcium phosphate were all passed through a #200 sieve, individually.
All three powders were intimately mixed in a suitable mixing apparatus. Novata B was melted in a stainless steel pot, keeping the temperature below 60'C.
The mixed powder was then added to the completely melted wax (around 50'C) with constant stirring. The temperature was then cooled slowly to 40'C and kept constant at that temperature. The uniform suspension was then transferred to a automated suppository filing kettle, and continuously stirred at 38'C.
After the fill weight was determined, the suppository shells were filled to the suggested fill weight at a temperature of about 37'C (e. g., between 36' - 38'Cj. The suppositories were allowed to cool, then sealed.
Dissolution results were then conducted using USP basket method, 50 rpm, in phosphate buffer at pH 6.8. The results are set~forth in Table 2.
_.. .__ _ ~_.__~~
_ .._ _ PERCENT MORPHINE SULPHATE DISSOLVED
Hour Formulation A Formulation B Formulation C

1 35.0 21.7 21.8 2 49.5 45.5 30.2 3 74.4 50.6 42.4 4 89.5 63.4 45.7 6 100.0 80.1 60.6 8 - 90.5 70.1 - 100.0 83.0 12 - - 92.7 In Example 1, the amount of alginate was about 18.2% the amount of calcium salt was about 1.81 %, and the amount of glyceride was about 78%, by weight of the composition In Example 2, the amount of alginate was about 22.75$ the amount of calcium slat was about 2.25% and the amount of glyceride was about 73.33% by weight of the composition.
In Example 3, the amount of alginate was about 25%, the amount of calcium salt was about 2.5%, and the amount of glyceride was about 70.83%, by weight of the composition.
From the above dissolution results, as it can been seen that by increasing the proportions of sodium alginate and calcium phosphate, the release of morphine sulphate can be extended, e.g.
to 6 to 12 hours.
EXAMPLES 4 and 5 Effect of Different Alginates The usefulness of the invention was further demonstrated by the preparation of morphine suppositories using different viscosity grade of alginates.
The following two formulations set forth in Table 3 were prepared using the same method described for Examples 1-3. Each composition included 22.5% alginate, 2.25% calcium salt, and 73.33% glyceride.

°

~0 652 10 Morphine Sulphate .5H20 30.0 mg 30.0 mg Protanal LF1'"' (Low Viscosity) 405.0 mg -Protanal SF~'''' (High Viscosity) - 405.0 mg Calcium Phosphate Dibasic 45.0 mg 45.0 mg Novata B 1320.0 ma 1320. ma Total Weight 1800.0 mg 1800.0 mg Dissolution results the results are set forth in for Examples 4 and 5 were then obtained using the U.S.P. basket method 50 rpm, in pH 6.8 Phosphate buffer.

Percenr Morphine Sulphate Dissolved Hour 1 19.3 15.6 2 32.8 25.1 3 45.8 37.0 4 57.8 43.0 6 78.7 64.9 8 88.0 71.2 when comparing the dissolution results of suppositories A
and B, it was observed that by using a high viscosity alginate, the release profile was sustained for a significantly longer period of time.
In Examples 6-8, controlled release suppositories of morphine sulphate were prepared in which the amount of drug is 30 mg, 60 mg and 100 mg, respectively. The following suppository formulations set forth in Table 5 (using the method described under Examples 1-3 above) were prepared.

_.. _..__ _______..._._~-.r-. ___-..___~

I~ctredient Morphine Sulphite .5H 30 mg 60 mg 100 mg Protanal SF 200'x"' 405 mg 360 mg 360 mg Calcium Phosphate Dibasic45 mg 36 mg 36 mg l~vata B 1320 ma 1344 ma 1304 ma Total 1800 mg 1800 mg 1800 mg In Example 6, the composition included 22.5% alginate, 2.25%
calcium salt, and 73.33% glyceride.
In Example 7, the composition included 20% alginate, 2%
calcium salt, and 74.66% glyceride.
In Example 8,~the composition included 20% alginate, 2%
calcium salt, and 72.44% glyceride.
The suppositories of Examplesl6-8 were then tested for dissolution using the USP basket method, 50 rpm, in pH 6.8 Phosphate buffer for 8 hours. The dissolution results are set forth in Table 6 below.

PERCENT MORPHINE sgULPHATE DISSOLVED
Hour 1 14.45 17.15 16.58 2 22.57 30.68 25.43 3 33.00 40.36 35.80 4 43.56 48.85 42.81 6 57.23 65.08 56.35 8 65.88 69.67 68.55 Thus, different strengths of morphine suppositories with controlled release characteristics can be manufactured by varying the proportions df the different ingredients in the controlled release system of the present invention.

ORAL CONTROLLED RELEASE SYSTEM
An oral controlled release composition according to the present invention was prepared with the formulation set forth in Table 7.

i _.
a v ~~ ~ N~ - r..~..._... .._..__..- _..._---- _._...__..........

Ingredient Weight (mg1 Dimenhydrinate 75 Protanol SF/200 75 (Sodium Alginate) Calcium Phosphate 7 Lactose (spray dried) 25 Cetostearyl Alcohol 30 Magnesium Stearate Talc Total 218 mg The dimenhydrinate, protanol, calcium phosphate and lactose were dry blended until thoroughly mixed. Cetostearyl alcohol was added to the warmed mixed powder, and the whole was mixed thoroughly. The mixture was allowed to cool in the air, regranulated and sieved through a 16 mesh screen.
The coated granules were filled in a hard gelatin capsule using talc and magnesium stearate as lubricants (capsules) or were compressed using appropriate punches (tablets).
Dissolution results of Example 9, using USP paddle method, 50 rpm were then obtained in deionized water. The results are set forth in Table 8.

Hour Percent of Dimenhydrinate Dissolved 1 15.00 2 29.00 3 47.00 4 70.00 77.00 6 91.00 In Example 10, the method of Example 9 was followed, except I
that the amount of cetostearyl alcohol was increased to 50 mg per ' capsule or tablet. Dissolution results of Example 10, using USP
paddle method, 50 rpm were then obtained in deionized water. The results are set forth in Table 9.

~~ 65210 .

Hour Percent of D,~menhyd~inate Dissolved 1 25.00 2 34.00 3 38.00 4 53.00 71.00 In Example 11, the method of Example 9 was followed except the amount of dimenhydrinate was decreased to 50 mg and the amount of lactose increased to 70 mg. Dissolution results of Example 11, using USP paddle method, 50 rpm were then obtained in deionized water. The results are set forth in Table 10.

Hour Percent of Dimenhydr;nat-A Dissolve 1 22.00 2 47.00 3 82.00 4 92.00 100.00 Bioavailability Comparison of Two Controlled Release Morphine' rcecZal 511DDOSSrnry~F'ormp at i nme A three-way crossover bioavailability study was conducted to compare two 30 mg morphine sulfate controlled release rectal suppositories. Exatr~ple 12 was formulated according to Example 5 (high viscosity alginate) and Example 13 was formulated according to Example 4 (low viscosity alginate) with the marketed MS Contin 30 mg tablet given orally.
Fourteen (14) healthy male volunteers received single 30 mg doses of each of the two suppositories and MS Contin'~' in randomized order, separated by a washout period of one week. In all phases, subjects maintained a reclining position for 1 hour and fasted for 4 hours following the dose. Preceding each rectal administration subjects were administered a Fleet enema and underwent~proctoscopic examinations before dosing and at the and of the blood sampling period. Blood samples were drawn prior to each dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours after the dose. Plasma was analyzed by a RIA method using antibodies that did not cross-react with the glucuronide metabolites. Mean plasma concentrations at each sampling time are depicted graphically in Figure 1.
Both suppositories produced excellent sustained release profiles. For Suppositories A and B, maximum plasma concentrations (Cmax) were 7.8 and 9.2 mg/ml respectively, compared to 10.4 mg/ml for MS contin. Curve width at half maximum plasma concentration (W5o) was approximately 10 hours for both suppositories versus 4.3 hours for MS Contin. Overall bioavailability (AUC 0-24) was 39% greater than MS Contin for Example 12 and 44% higher for Example 13. This increased bioavailability is possibly the result of avoidance or reduction of the "first-pass" effect. Between-subject variability in bioavailability was greater for both suppository formulations than for orally-administered MS Contin tablets.
No serious or unexpected adverse reactions were noted for any of the formulations. Adverse experiences were reported in 2 subjects following Example 12, in 6 subjects after Example 13, and in 4 subjects after MS Contin (Table 2). The post-dose proctoscopic findings were limited to mild erythema in 6 subjects following Example 12 and 5 subjects after Example 13 (for two of these latter subjects, mild erythema was also reported pre-dose).
i Based on the foregoing results, either suppository would be suitable formulation. The effects of the difference in alginate viscosity between the two suppository formulations appeared to be primarily limited to Cmax, in that, for the high viscosity Example 12, Cmax was approximately 85% of that observed with Example 13. Since side effects may have been associated with the ..igher peak concentration of Example 13 and, at steady state, peak concentrations will be even higher, it is considered that the formulation with the lower Cmax (Example 12) may offer a greater margin of safety.
While the invention has been illustrated with respect to the foregoing examples, different drugs, alginic acids, salts of multivalent ions and excipients (including suppository bases) can be substituted. Such variations and modifications thereof can be made without departing from the spirit and scope of the invention, and are contemplated to be within the scope of the appended claims.

Claims (33)

1. A controlled release pharmaceutical composition for rectal administration in humans or animals, comprising:
a controlled release matrix comprising a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium salt selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate, calcium gluconate and mixtures of any of the foregoing, a therapeutically active agent; and a suitable vehicle which melts or dissolves in rectal fluids, said calcium salt cross-linking with the sodium alginate and thereby controlling the release of said therapeutically active agent from said matrix when said vehicle melts or dissolves.
2. The composition of claim 1, wherein the sodium alginate comprises from about 10 to about 50 percent of said composition by weight, and the amount of calcium salt is from about 2 to about 12 percent by weight of the sodium alginate in the composition.
3. The composition of claim 1, wherein said vehicle is a fatty acid wax selected from the group consisting of mono-, di- and triglycerides of saturated, natural fatty acids of the chain length C12 to C18.
4. The composition of claim 3, wherein said vehicle comprises from about 20 to about 90 percent of said composition, by weight.
5. The composition of claim 3, wherein said vehicle comprises from about 65 to about 80 percent of said composition, by weight.
6. The composition of claim 5, wherein the sodium alginate comprises from about 15 to about 30 percent of said composition by weight.
7. The composition of claim 1, wherein the sodium alginate has a viscosity from about 40 to about 150 cps as a 1 percent solution.
8. The composition of claim 1, wherein the sodium alginate has a viscosity from about 300 to about 500 cps as a 1 percent solution.
9. The composition of claim 1, wherein the sodium alginate has a particle size from about 45 to about 125 microns.
10. The composition of claim 1, wherein the calcium salt comprises from about 1 to about 4% by weight of said composition.
11. The composition of claim 3, wherein said fatty acid wax has a melting point in the range of from about 29°C to about 42°C.
12. The composition of claim 1, wherein said therapeutically active agent is amitriptyline, atropine, chlorpromazine, codeine, diclofenac, diphenhydramine, doxylamine, ephedrine, hyoscyamine, morphine, metoclopramide, hydromorphone, naproxyn, oxycodone, papaverine, phenyl-propanolamine, propranolol, quinidine, scopolamine, theophylline, or thioridazine.
13. A method for providing a controlled release suppository containing a pharmaceutically active agent for rectal administration in humans and animals, comprising:
combining a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate and calcium gluconate in an amount effective to cross-link with the sodium alginate, and an effective amount of a therapeutically active agent; and adding the mixture to a sufficient quantity of a suitable melted vehicle and then preparing suppositories.
14. A controlled release pharmaceutical composition for oral administration, comprising:
a controlled release matrix comprising a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt which crass-links with the sodium alginate when said composition is exposed to aqueous solutions, and a higher aliphatic alcohol containing from about 8 to 18 carbon atoms;
and an effective amount of an active agent distributed or suspended in said controlled release matrix, said higher aliphatic alcohol being in a predetermined amount to obtain a desired rate of release of said active agent from said matrix when said composition is exposed to aqueous solutions.
15. The composition of claim 14, wherein the sodium alginate comprises from about l0 to about 50 percent by weight of said composition, and the calcium salt comprises from about 1 to about 12 percent by weight of the sodium alginate present in the composition.
16. The composition of claim 14, wherein the sodium alginate is an amount from about 15 to about 30 percent by weight of the composition.
17. The composition of claim 14, wherein said calcium salt is selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate and calcium gluconate.
18. The composition of claim 14, wherein said pharmaceutical agent is amitriptyline, atropine, chlorpromazine, codeine, diclofenac, diphenhydramine, doxylamine, ephedrine, hyoscyamine, morphine, metoclopramide, hydromorphone, naproxyn, oxycodone, papaverine, phenyl-propanolamine, propranolol, quinidine, scopolamine, theophylline or thioridzine.
19. The composition of claim 14, further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, polyhydric alcohols, and mixtures of the foregoing.
20. The composition of claim 19, wherein said composition is filled into a capsule.
21. The composition of claim 19, wherein said composition is granulated and compressed into a tablet.
22. A controlled release matrix for the release of an orally administered therapeutically active agent, comprising:
from abo0ut 10 to about 50 percent by weight of a pharmaceutically acceptable sodium alginate;
a sufficient amount of a pharmaceutically acceptable calcium salt to cross-link with said sodium alginate when said matrix is exposed to aqueous solutions or gastric fluid; and a predetermined amount of a higher aliphatic alcohol to obtain a desired rate of release of an active agent to be incorporated into said matrix, said higher aliphatic alcohol containing from about 8 to about 18 carbon atoms.
23. A method for providing a controlled release suppository containing a pharmaceutically active agent for rectal administration in humans and animals, comprising:
combining a pharmaceutically acceptable sodium alginate, a pharmaceutically acceptable calcium salt in an amount effective to cross-link with the sodium alginate, and an effective amount of a therapeutically active agent; and adding the mixture to a sufficient quantity of a suitable melted vehicle and then preparing suppositories.
24. A method of providing an orally administered controlled release composition for a therapeutically active agent, comprising:
preparing a controlled release matrix by combining a pharmaceutically acceptable sodium alginate with a pharmaceutically acceptable calcium salt capable of cross-linking the sodium alginate when exposed to aqueous solutions, and a higher aliphatic alcohol containing from about 8 to about 18 carbon atoms;
adding an effective amount of a therapeutically active agent to the matrix such that said therapeutically active agent is suspended or distributed in said matrix; and including a sufficient amount of said calcium salt and higher aliphatic alcohol to control the release of said therapeutically active agent from said matrix at a desired rate when said composition is exposed to aqueous solutions.
25. The use of the composition of any one of claims 1 to 12 to control the release of a pharmaceutical composition administered rectally to a human or animal.
26. The use of the composition of any one of claims 14 to 21 to control the release of a pharmaceutical composition administered orally to a human or animal.
27. A method for providing a controlled release suppository containing a pharmaceutically active agent for rectal administration in humans and animals, comprising:
combining a controlled release matrix consisting essentially of a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium salt selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate, calcium gluconate and mixtures of any of the foregoing with an effective amount of a therapeutically active agent to provide a therapeutic effect;
adding the mixture to a sufficient quantity of a suitable melted vehicle and then preparing suppositories; and including the calcium salt in an effective amount to cross-link the sodium alginate and thereby provide a controlled release of the therapeutically active agent when said vehicle melts or dissolves.
28. The controlled release pharmaceutical composition of claim 14 wherein said controlled release matrix consists essentially of said sodium alginate, said calcium salt and said higher aliphatic alcohol.
29. The controlled release matrix of claim 22 consisting essentially of said sodium alginate, said calcium salt and said higher aliphatic alcohol.
30. A controlled release pharmaceutical composition for oral administration, comprising:
a) a controlled release matrix consisting essentially of:
i) a pharmaceutically acceptable sodium alginate;
ii) a pharmaceutically acceptable calcium salt which cross-links with the sodium alginate when said composition is exposed to aqueous solutions;
iii) a higher aliphatic alcohol containing from about 8 to about 18 carbon atoms;
iv) an effective amount of an active agent distributed or suspended in said controlled release matrix;
said sodium alginate comprising from about 10 to about 50 percent by weight of said composition, and said calcium salt comprising from about 2 to about 12 percent by weight of said sodium alginate present in said composition; and said higher aliphatic alcohol being in a predetermined amount to obtain a desired rate of release of said active agent from said matrix when said composition is exposed to aqueous solutions; and b) one or more inert diluents.
31. The composition of claim 30, wherein said inert diluent is selected from the group consisting of monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof.
32. A controlled release pharmaceutical composition for oral administration, comprising a controlled release matrix consisting essentially of:
i) a pharmaceutically acceptable sodium alginate;
ii) a pharmaceutically acceptable calcium salt which cross-links with the sodium alginate when said composition is exposed to aqueous solutions;
iii) a higher aliphatic alcohol containing from about 8 to about 18 carbon atoms;
iv) an effective amount of an active agent distributed or suspended in said controlled release matrix; and v) one or more inert diluents;
said sodium alginate comprising from about 10 to about 50 percent by weight of said composition, and said calcium salt comprising from about 2 to about 12 percent by weight of said sodium alginate present in said composition; and said higher aliphatic alcohol being in a predetermined amount to obtain a desired rate of release of said active agent from said matrix when said composition is exposed to aqueous solutions.
33. The composition of claim 32, wherein said inert diluent is selected from the group consisting of monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof.
CA 2065210 1991-09-11 1992-04-06 Controlled release matrix for pharmaceuticals Expired - Lifetime CA2065210C (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US758,883 1991-09-11
US07/758,883 US5215758A (en) 1991-09-11 1991-09-11 Controlled release matrix suppository for pharmaceuticals

Publications (2)

Publication Number Publication Date
CA2065210A1 CA2065210A1 (en) 1993-03-12
CA2065210C true CA2065210C (en) 2000-08-29

Family

ID=25053475

Family Applications (1)

Application Number Title Priority Date Filing Date
CA 2065210 Expired - Lifetime CA2065210C (en) 1991-09-11 1992-04-06 Controlled release matrix for pharmaceuticals

Country Status (13)

Country Link
US (2) US5215758A (en)
EP (2) EP0698389B1 (en)
JP (2) JP3034125B2 (en)
KR (2) KR100203339B1 (en)
AT (2) AT145820T (en)
AU (1) AU653048B2 (en)
CA (1) CA2065210C (en)
DE (4) DE69215612T2 (en)
DK (2) DK0531611T3 (en)
ES (2) ES2139798T3 (en)
GR (1) GR3022572T3 (en)
IL (2) IL101758A (en)
ZA (1) ZA9203417B (en)

Families Citing this family (105)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070275062A1 (en) * 1993-06-18 2007-11-29 Benjamin Oshlack Controlled release oxycodone compositions
US5266331A (en) * 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
US20080075781A1 (en) * 1992-11-25 2008-03-27 Purdue Pharma Lp Controlled release oxycodone compositions
EP0652745A1 (en) * 1992-07-31 1995-05-17 Daratech Pty. Ltd. Controlled release implants
US5891471A (en) 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
US5849240A (en) 1993-11-23 1998-12-15 Euro-Celtique, S.A. Method of preparing sustained release pharmaceutical compositions
IL119660A (en) 1993-05-10 2002-09-12 Euro Celtique Sa Controlled release formulation comprising tramadol
US5662933A (en) * 1993-09-09 1997-09-02 Edward Mendell Co., Inc. Controlled release formulation (albuterol)
US5773025A (en) * 1993-09-09 1998-06-30 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems--amorphous drugs
US6726930B1 (en) 1993-09-09 2004-04-27 Penwest Pharmaceuticals Co. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5455046A (en) * 1993-09-09 1995-10-03 Edward Mendell Co., Inc. Sustained release heterodisperse hydrogel systems for insoluble drugs
US5843480A (en) 1994-03-14 1998-12-01 Euro-Celtique, S.A. Controlled release diamorphine formulation
US5670163A (en) * 1994-06-20 1997-09-23 Kv Pharmaceuticals Company Long acting GI and esophageal protectant
US5554379A (en) * 1994-06-20 1996-09-10 Kv Pharmaceutical Company Long acting GI and esophageal protectant
US5554380A (en) * 1994-08-04 1996-09-10 Kv Pharmaceutical Company Bioadhesive pharmaceutical delivery system
GB9422154D0 (en) 1994-11-03 1994-12-21 Euro Celtique Sa Pharmaceutical compositions and method of producing the same
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
GB9710767D0 (en) * 1996-06-26 1997-07-23 On Ninh Analgesic and anti-inflamatory compositions comprising domperidone and methods of using same
ES2322405T3 (en) 1996-07-08 2009-06-19 Penwest Pharmaceuticals Co. Matrix controlled to high doses insoluble drugs release.
US6656508B2 (en) * 1997-04-17 2003-12-02 Amgen Inc. Sustained-release alginate gels
US5989571A (en) * 1997-07-23 1999-11-23 Millenium Pharmaceutical Technologies, Inc. Contact dermatitis pharmaceutical preparation with anti-histamine and anti-inflammatory
US6056977A (en) 1997-10-15 2000-05-02 Edward Mendell Co., Inc. Once-a-day controlled release sulfonylurea formulation
DK1041987T3 (en) 1997-12-22 2006-08-21 Euro Celtique Sa An oral pharmaceutical dosage form comprising a combination of an opioid agonist and naltrexone
CA2314896C (en) * 1997-12-22 2005-09-13 Euro-Celtique, S.A. A method of preventing abuse of opioid dosage forms
US7022683B1 (en) * 1998-05-13 2006-04-04 Carrington Laboratories, Inc. Pharmacological compositions comprising pectins having high molecular weights and low degrees of methoxylation
GB9816899D0 (en) 1998-08-05 1998-09-30 Boots Co Plc Therapeutic agents
DE69928472T2 (en) 1998-08-07 2006-08-10 Curis, Inc., Cambridge Stabilized pharmaceutical compositions of hedgehog proteins and their use
US6200590B1 (en) 1998-08-10 2001-03-13 Naphcare, Inc. Controlled, phased-release suppository and its method of production
US6368625B1 (en) 1998-08-12 2002-04-09 Cima Labs Inc. Orally disintegrable tablet forming a viscous slurry
JP2002525311A (en) * 1998-10-01 2002-08-13 エラン ファーマ インターナショナル,リミティド Controlled release nanoparticle composition
US8236352B2 (en) * 1998-10-01 2012-08-07 Alkermes Pharma Ireland Limited Glipizide compositions
US8293277B2 (en) 1998-10-01 2012-10-23 Alkermes Pharma Ireland Limited Controlled-release nanoparticulate compositions
US20040115134A1 (en) * 1999-06-22 2004-06-17 Elan Pharma International Ltd. Novel nifedipine compositions
DE19918325A1 (en) 1999-04-22 2000-10-26 Euro Celtique Sa Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives
US6225343B1 (en) * 1999-06-16 2001-05-01 Nastech Pharmaceutical Company, Inc. Compositions and methods comprising morphine gluconate
AU762291B2 (en) * 1999-09-30 2003-06-19 Penwest Pharmaceutical Co. Sustained release matrix systems for highly soluble drugs
CA2400578C (en) 2000-02-08 2007-01-02 Euro-Celtique, S.A. Controlled-release compositions containing opioid agonist and antagonist
IL151057D0 (en) * 2000-02-08 2003-04-10 Euro Celtique Sa Tamper-resistant oral opioid agonist formulations
US20040033241A1 (en) * 2000-06-02 2004-02-19 Allergan, Inc. Controlled release botulinum toxin system
US20050214327A1 (en) * 2000-06-02 2005-09-29 Allergan, Inc. Neurotoxin-containing suppositories and related methods
US20020044962A1 (en) * 2000-06-06 2002-04-18 Cherukuri S. Rao Encapsulation products for controlled or extended release
US7198795B2 (en) 2000-09-21 2007-04-03 Elan Pharma International Ltd. In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions
US7494669B2 (en) * 2001-02-28 2009-02-24 Carrington Laboratories, Inc. Delivery of physiological agents with in-situ gels comprising anionic polysaccharides
US6777000B2 (en) * 2001-02-28 2004-08-17 Carrington Laboratories, Inc. In-situ gel formation of pectin
US6720356B2 (en) * 2001-04-20 2004-04-13 Spencer Feldman Magnesium di-potassium EDTA complex and method of administration
AU2002303614B2 (en) * 2001-05-02 2005-02-10 Euro-Celtique S.A. Once-a-day oxycodone formulations
US20110104214A1 (en) 2004-04-15 2011-05-05 Purdue Pharma L.P. Once-a-day oxycodone formulations
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
EP1406630A1 (en) * 2001-07-06 2004-04-14 Endo Pharmaceuticals Inc. Parenteral administration of 6-hydroxy-oxymorphone for use as an analgesic
WO2003007802A2 (en) * 2001-07-18 2003-01-30 Euro-Celtique, S.A. Pharmaceutical combinations of oxycodone and naloxone
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
EP1414451B1 (en) 2001-08-06 2009-05-20 Euro-Celtique S.A. Opioid agonist formulations with releasable and sequestered antagonist
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
US20030157168A1 (en) * 2001-08-06 2003-08-21 Christopher Breder Sequestered antagonist formulations
JP2005508939A (en) * 2001-10-12 2005-04-07 エラン ファーマ インターナショナル,リミティド Compositions having a combination of immediate release and sustained release properties
US20030091630A1 (en) * 2001-10-25 2003-05-15 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data
US20030152622A1 (en) * 2001-10-25 2003-08-14 Jenny Louie-Helm Formulation of an erodible, gastric retentive oral diuretic
US6585996B1 (en) 2002-03-13 2003-07-01 Westlake Laboratories, Inc. Lipid-soluble thiamine derivatives in the treatment of autism
CN100411611C (en) 2002-04-05 2008-08-20 欧洲凯尔蒂克公司 Matrix for sustained, invariant and independent release of active compounds
US20050020613A1 (en) * 2002-09-20 2005-01-27 Alpharma, Inc. Sustained release opioid formulations and method of use
EP2422775A3 (en) 2002-09-20 2012-04-18 Alpharma, Inc. Sequestering subunit and related compositions and methods
EP2329813A1 (en) * 2002-11-26 2011-06-08 University of Maryland, Baltimore Aqueous sustained-release drug delivery system for highly water-soluble electrolytic drugs
US20040202717A1 (en) * 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
MY135852A (en) * 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
WO2005020933A2 (en) * 2003-09-02 2005-03-10 University Of South Florida Nanoparticles for drug-delivery
ES2344350T3 (en) 2003-09-25 2010-08-25 Euro-Celtique S.A. pharmaceutical combinations of hydrocodone and naltrexone.
EP1663229B1 (en) 2003-09-25 2010-04-14 Euro-Celtique S.A. Pharmaceutical combinations of hydrocodone and naltrexone
TWI483944B (en) * 2004-03-30 2015-05-11 Euro Celtique Sa Oxycodone hydrochloride composition,pharmaceutical dosage form,sustained release oral dosage form,and pharmaceutically acceptable package having less than 25 ppm 14-hydroxycodeinone
EP1604666A1 (en) * 2004-06-08 2005-12-14 Euro-Celtique S.A. Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD)
US9308164B2 (en) 2004-06-30 2016-04-12 Sovereign Pharmaceuticals, Llc Hyoscyamine dosage form
EP1702558A1 (en) * 2005-02-28 2006-09-20 Euro-Celtique S.A. Method and device for the assessment of bowel function
US20070082050A1 (en) * 2005-05-31 2007-04-12 Cherukuri S R Modified release formulations of antihypertensive drugs
KR100730321B1 (en) 2005-09-30 2007-06-19 한국콜마 주식회사 A cosmetic composition of 2 agent and gel patch type for skin lifting, method for manufacturing and using the same
SE530184C2 (en) * 2005-12-23 2008-03-18 Kjell Stenberg Bioadhesive pharmaceutical film composition containing low viscosity alginates
JP5429703B2 (en) * 2005-12-30 2014-02-26 モル リサーチ アプリケーションズ リミテッド Apparatus for the treatment of anal sphincter
US20070190141A1 (en) * 2006-02-16 2007-08-16 Aaron Dely Extended release opiate composition
US20070286884A1 (en) * 2006-06-13 2007-12-13 Xylos Corporation Implantable microbial cellulose materials for hard tissue repair and regeneration
HUE032156T2 (en) 2006-06-19 2017-09-28 Alpharma Pharmaceuticals Llc Pharmaceutical compositions
US20080020032A1 (en) * 2006-07-21 2008-01-24 Michael Crowley Hydrophobic abuse deterrent delivery system for hydromorphone
GB0624880D0 (en) * 2006-12-14 2007-01-24 Johnson Matthey Plc Improved method for making analgesics
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
EP2224808A4 (en) * 2007-12-17 2013-11-27 Alpharma Pharmaceuticals Llc Pharmaceutical composition
PE04222011A1 (en) * 2008-07-07 2011-07-01 Euro Celtique Sa pharmaceutical composition comprising opioid antagonists
PT2349250T (en) * 2008-10-31 2017-07-25 Lipid Pharmaceuticals Ehf Fatty acids for use as a medicament
US20100151014A1 (en) * 2008-12-16 2010-06-17 Alpharma Pharmaceuticals, Llc Pharmaceutical composition
MY152279A (en) 2009-03-10 2014-09-15 Euro Celtique Sa Immediate release pharmaceutical compositions comprising oxycodone and naloxone
EP2445481B1 (en) 2009-06-18 2017-03-22 Rdd Pharma Ltd. Methods and devices for delivery of pharmaceutical agents within orifices of the body
US20130190299A1 (en) 2010-06-30 2013-07-25 Victoria Link Ltd. Methods and compositions for treatment of multiple sclerosis
UA114887C2 (en) 2010-12-22 2017-08-28 Пюрдю Фарма Л.П. Encased tamper resistant controlled release dosage forms
NZ612996A (en) 2010-12-23 2015-05-29 Purdue Pharma Lp Tamper resistant solid oral dosage forms
SG11201407988UA (en) 2012-07-16 2015-01-29 Rhodes Technologies Process for improved opioid synthesis
EP2877473B1 (en) 2012-07-16 2017-06-14 Rhodes Technologies Process for improved opioid synthesis
CN102823585B (en) * 2012-08-28 2014-06-25 中国农业科学院农业环境与可持续发展研究所 Sustained-release preparation for water-soluble pesticide and preparation method of sustained-release preparation
JP6208261B2 (en) 2013-02-05 2017-10-04 パーデュー、ファーマ、リミテッド、パートナーシップPurdue Pharma L.P. Tampering resistant pharmaceutical preparations
WO2014140899A2 (en) 2013-03-15 2014-09-18 Johnson Matthey Public Limited Company Morphine sulfate methanolic solvate, processes for making same and related compositions and methods for treating pain
US20140271896A1 (en) 2013-03-15 2014-09-18 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
JP2016525138A (en) 2013-07-23 2016-08-22 ユーロ−セルティーク エス.エイ. The combination of oxycodone and naloxone for use in the treatment of pain in patients suffering from diseases increase the risk for diseases and / or Enterobacteriaceae migration results in pain and intestinal Disconnect bio cis
EP3027622B1 (en) 2013-08-02 2019-04-03 Johnson Matthey Public Limited Company Process for the preparation of oxymorphone
EP3082770A1 (en) * 2013-12-20 2016-10-26 Disphar International B.V. Dry enema product
CN106029670A (en) 2014-01-15 2016-10-12 罗德科技公司 Process for improved oxycodone synthesis
AU2015207734B2 (en) 2014-01-15 2017-02-23 Rhodes Technologies Process for improved oxymorphone synthesis
US9062063B1 (en) 2014-03-21 2015-06-23 Johnson Matthey Public Limited Company Forms of oxymorphone hydrochloride
US9918979B2 (en) 2015-01-29 2018-03-20 Johnson Matthey Public Limited Company Process of preparing low ABUK oxymorphone hydrochloride
US9145420B1 (en) 2015-03-27 2015-09-29 Johnson Matthey Public Limited Company Crystalline forms of morphine sulfate
US10196355B2 (en) 2016-06-20 2019-02-05 Johnson Matthey Public Limited Company Forms of apremilast

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3629393A (en) * 1969-09-11 1971-12-21 Nikken Chemicals Co Ltd Release-sustaining-tablet
US4717713A (en) * 1983-10-31 1988-01-05 Research Corporation Controlled release liquid pharmaceutical
JPH0684296B2 (en) * 1987-12-21 1994-10-26 花王株式会社 Multilayer suppository
US5110605A (en) * 1990-08-21 1992-05-05 Oramed, Inc. Calcium polycarbophil-alginate controlled release composition and method
US5102666A (en) * 1990-09-11 1992-04-07 Oramed, Inc. Calcium polycarbophil controlled release composition and method

Also Published As

Publication number Publication date
ES2139798T3 (en) 2000-02-16
US5215758A (en) 1993-06-01
CA2065210A1 (en) 1993-03-12
JPH05148159A (en) 1993-06-15
AT187887T (en) 2000-01-15
ES2097826T3 (en) 1997-04-16
JP3624123B2 (en) 2005-03-02
ZA9203417B (en) 1993-01-27
AT145820T (en) 1996-12-15
AU653048B2 (en) 1994-09-15
IL101758D0 (en) 1992-12-30
IL117356A (en) 2000-08-31
IL101758A (en) 1996-12-05
EP0698389B1 (en) 1999-12-22
DE69230475D1 (en) 2000-01-27
DK0698389T3 (en) 2000-05-01
DE69215612T2 (en) 1997-05-15
KR100225493B1 (en) 1999-10-15
JP3034125B2 (en) 2000-04-17
US5508043A (en) 1996-04-16
IL117356D0 (en) 1996-07-23
DK0531611T3 (en) 1997-05-26
EP0698389A1 (en) 1996-02-28
DE69230475T2 (en) 2000-07-13
KR100203339B1 (en) 1999-06-15
AU2107392A (en) 1993-03-18
GR3022572T3 (en) 1997-05-31
DE69215612D1 (en) 1997-01-16
EP0531611B1 (en) 1996-12-04
EP0531611A1 (en) 1993-03-17
JP2000136149A (en) 2000-05-16

Similar Documents

Publication Publication Date Title
ES2308675T3 (en) Hydromorphone formulations extruded administrable orally fusion.
DE69911240T2 (en) Compositions containing micronized eplerenone
US5656295A (en) Controlled release oxycodone compositions
EP0257915B1 (en) Pharmaceutical formulations comprising microcapsules
US6403120B1 (en) Extended release formulation of venlafaxine hydrochloride
JP4012689B2 (en) A new sustained-release oral formulation
US5773025A (en) Sustained release heterodisperse hydrogel systems--amorphous drugs
AU741992B2 (en) Fast disintegrating tablets
CA2140254C (en) Controlled release morphine preparation
KR100205276B1 (en) Sustained-release tablet
CA1272134A (en) Drug delivery system
RU2136283C1 (en) Preparation of controlled drug release and method of its preparing, method of treatment
US4880830A (en) Slow release formulation
JP4943975B2 (en) Methods for preparing fenofibrate pharmaceutical compositions and it has a high bioavailability
US6517866B1 (en) Sertraline salts and sustained-release dosage forms of sertraline
US6136343A (en) Sustained release heterodisperse hydrogel systems for insoluble drugs
CA2042289C (en) Taste masking and sustained release coatings for pharmaceuticals
AU781058B2 (en) Delayed-action form of administration containing tramadol saccharinate
US4609675A (en) Stable, high dose, high bulk density ibuprofen granulations for tablet and capsule manufacturing
JP3267561B2 (en) Tramadol or use and analgesic agents of the pharmaceutically acceptable salt thereof
US8506998B2 (en) Pharmaceutical formulation
JP3560244B2 (en) Pharmaceutical dosage form and a preparation of the solid in the form of release in two stages over a long period of time
US4424235A (en) Hydrodynamically balanced controlled release compositions containing L-dopa and a decarboxylase inhibitor
JP4943581B2 (en) Method for producing a rapidly dispersing solid oral dosage forms
US5399357A (en) Sustained release preparations

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry