GB2260080A - Gelled alginate compositions - Google Patents

Gelled alginate compositions Download PDF

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Publication number
GB2260080A
GB2260080A GB9121219A GB9121219A GB2260080A GB 2260080 A GB2260080 A GB 2260080A GB 9121219 A GB9121219 A GB 9121219A GB 9121219 A GB9121219 A GB 9121219A GB 2260080 A GB2260080 A GB 2260080A
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GB
United Kingdom
Prior art keywords
pharmaceutical
alginate
gelled alginate
gelled
beads
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB9121219A
Other versions
GB9121219D0 (en
Inventor
Michael Hannay
Debra Anne Lingham
John David Lord
Robert Rona
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.)
Rhone Poulenc Rorer Ltd
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Rhone Poulenc Rorer Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer Ltd filed Critical Rhone Poulenc Rorer Ltd
Priority to GB9121219A priority Critical patent/GB2260080A/en
Publication of GB9121219D0 publication Critical patent/GB9121219D0/en
Publication of GB2260080A publication Critical patent/GB2260080A/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Abstract

A gelled alginate which comprises a pharmaceutical and, as a release-modifying adjuvant, a pharmaceutically acceptable excipient such as polyethylene glycols, polyoxyethylene sorbitan fatty acid esters, Gelucires, vegetable oils and surfactants.

Description

NEW COMPOSITIONS This invention relates to the encapsulation of pharmaceuticals within alginates.
Alginates are polysaccharides which are generally isolated from marine brown algae. The alginic acids generally contain approximately equal proportions of polymannurose segments and alternating segments and small proportions of polygulurose segments. The structure of alginic acid from different sources may vary. Alginic acid may also contain a high proportion of polygulurose segments, an intermediate proportion of alternating segments, and a small proportion of polymannurose. Such differences in structure give rise to differences in the properties and functionality of alginates isolated from different brown algae.
Alkali metal and ammonium salts of alginic acid, such as sodium alginate, are water-soluble. Alginic acid itself, as well as salts with polyvalent cations such as calcium, are substantially water-insoluble.
Alginic acid derivatives have been widely used in the food and pharmaceutical industries as dispersing, thickening and disintegrating agents. They have been used in the food industry to encapsulate fruit juices to simulate berries, and have also been used to produce sausage skins. Alginates have also been used to immobilise cells and enzymes.
The ability of alginates to form edible gels by reaction with calcium salts has been exploited in the encapsulation of various materials. Oily substances alone have been encapsulated, for example fish oils to produce simulated caviar or flavouring agents.
Insoluble active substances alone have been dispersed in alginate beads to improve dispersion, taste, handling characteristics such as powder flow, and also to control the release of the active substance.
If liquid materials such as oils are incorporated into alginate beads then further coating of the beads may be carried out in order to prevent leakage.
It has, however, not previously been possible to encapsulate pharmaceuticals in alginate gels and to control the rate of release of the pharmaceutical from the gel by inclusion of release-modifying adjuvants.
The present invention provides a gelled alginate which comprises a pharmaceutical and, as a releasemodifying adjuvant, a pharmaceutically acceptable excipient. The pharmaceutical may be acidic, basic or neutral, water-soluble or water-insoluble and is generally solid at ambient temperature.
The pharmaceutical may be hydrophobic or hydrophilic. The formulation of pharmaceuticals which are both hydrophobic and insoluble in aqueous media to give suitable dissolution characteristics has, in the past, proved difficult.
The invention is particularly suitable for use with hydrophobic, water-insoluble pharmaceuticals.
Examples of hydrophilic water-soluble pharmaceuticals are chlorpromazine hydrochloride, chloroquine phosphate and trimipramine maleate.
Examples of hydrophobic poorly water-soluble pharmaceuticals are ketoprofen, dapsone, sulphathizole, paracetamol and 2-n-octadecylindole-5-carboxylic acid which is a hydrophobic pharmaceutical useful in the treatment of hyperlipidaemia.
High concentrations of active ingredient may be incorporated into the gelled alginate. The content of pharmaceutical will generally be from 0.1 to 98% w/w, preferably from 5 to 40 % w/w, most preferably about 20% w/w. These percentages refer to the content of pharmaceutical in the gelled alginate after drying. Using a 2% w/v sodium alginate solution with a viscosity of 40-60 mPa.s the maximum amount of pharmaceutical is generally 98% w/w of the dried bead.
The alginate content in the gelled alginate is generally from 1 to 98% w/w, preferably from 1 to 40% w/w, most preferably about 20% w/w.
The content of release modifying adjuvant is generally from 1 to 98% w/w, preferably from 5 to 80% w/w, most preferably about 60% w/w.
The gelled alginate of the present invention, in the form of beads, may be prepared by (a) contacting a first aqueous composition comprising a water-soluble alginate and a release-modifying adjuvant and, optionally, a pharmaceutical and (b) a second aqueous composition comprising a water-soluble polyvalent metal salt and, optionally, a pharmaceutical, at least one of the first and second compositions comprising pharmaceutical.
The pharmaceutical and adjuvant may be present in solution, emulsion or suspension. Sodium alginate is the preferred water-soluble alginic acid salt. The polyvalent metal salt is preferably a calcium salt, most preferably calcium lactate.
The concentration of the water-soluble alginic acid salt is preferably about 2% w/v.
The concentration of polyvalent metal salt is preferably about 4% w/v.
The process may be carried out above or below ambient temperature but is preferably carried out at ambient temperature. When the release modifying adjuvant is a solid which melts above room temperature the melted adjuvant may be added to the first aqueous composition and the resultant mixture agitated to form an emulsion or suspension. The emulsion or suspension is then added, for example, dropwise to the second aqueous composition comprising, eg calcium lactate. It is not generally necessary to adjust the pH of either solution to enable bead formation to take place.
The process may be carried out, for example, by dropping an aqueous solution of alginic acid salt comprising a pharmaceutical and a release modifying adjuvant into an aqueous solution containing the polyvalent metal salt. Beads or microcapsules are formed substantially immediately and can be separated and dried to form hard beads.
When a pharmaceutical is highly water soluble it may be lost from the alginate during gelling. Such loss can be reduced or avoided by incorporating the pharmaceutical into the metal salt solution as well as into the alginate solution.
The dried beads are approximately spherical and preferably have diameters in the range of 50 to 4000y, more preferably from 150 to 1500ss. In general smaller bead sizes are preferred.
The excipients are generally incorporated into the alginate solution as release modifying adjuvants in order to modify the properties of the microcapsules or beads eventually obtained. Such materials may modify the stability, rate of dissolution or dispersion or the bioavailability of the pharmaceutical. They may also reduce or eliminate leakage from the microcapsule, or optimize the incorporation of hydrophilic pharmaceuticals into the microcapsules.
The excipient may be solid or liquid at ambient temperatures. Solids are preferred.
The excipients may be water soluble or insoluble, or water-miscible or immiscible.
In general hydrophilic excipients facilitate or increase the dissolution rate of pharmaceuticals from alginate beads whereas hydrophobic excipients tend to retard their release.
Excipients which may be included in the alginate solution as release modifying adjuvants and thereby incorporated into the dried microcapsules include the following: (a) water-soluble hydrophilic solids eg Polyethylene glycols (PEGs) with a MW > 1500, fatty acid esters eg Gelucires with an HLB greater than 11; (b) water-soluble hydrophilic liquids eg low MW PEGs < 600, eg PEG 200 or PEG 400, polyoxyethylene sorbitan fatty acid esters, eg Tween 80, polyoxyethylene castor oil derivatives, eg Cremophor EL; (c) water-insoluble hydrophobic solids, eg Gelucires with an HLB less than 9; (d) water-insoluble hydrophobic liquids, eg vegetable, mineral and fixed oils, eg soya bean oil, arachis oil, coconut oil, olive oil, self emulsifying glyceryl monostearate (medium chain triglyceride), eg Inwitor 708; fractionated coconut oil (esters of medium chain fatty acids), eg Miglyol 812; apricot kernel oil Peg-6 complex, eg Labrafil M1994S and Labrafil M2125CS; and surfactants, eg sorbitan esters or soya lecithin.
The references to HLB values above are in accordance with the known Hydrophile-Lipophile Balance (HLB) system originally introduced to classify emulsifiers.
The system can be extended to certain release modifying adjuvants, in particular Gelucires. A Gelucire which is lipophilic will have an HLB number below 9: a Gelucire which is hydrophilic will have an HLB number greater than 11. Gelucires having HLB numbers in the range 9 to 11 are intermediate or water dispersible.
Polyethylene glycols and Gelucires are preferred and may be used alone or in conjunction with other releasemodifying adjuvants such as absorbable triglycerides and oils.
Other materials which may be included are: Solvents: isopropyl myristate, benzyl alcohol, benzyl benzoate, glycofurol, glycerin formal, propylene glycol, ethanol, isopropyl alcohol; pH adjusting agents: hydrochloric acid, sodium hydroxide, acetic acid, sodium (or potassium) acetate, sodium (or potassium) bicarbonate, sodium (or potassium) carbonate, sodium (or potassium) dihydrogen phosphate, disodium (or potassium) hydrogen phosphate; and Others: sugars, eg glucose, polyhydric alcohols, eg sorbitol, salts, eg sodium chloride, colloidal silicon dioxide, eg Aerosil 200, bile salts, eg sodium deoxycholate, sodium lauryl sulphate.
The following Examples illustrate the invention.
EXAMPLE 1 Encapsulation of Dapsone and Soya Bean Oil To a 2% w/v solution of sodium alginate 10% w/v soya bean oil and 3% w/v Dapsone were added. The resultant mixture was agitated to form a dispersion which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 2 Encapsulation of Dapsone Soya Bean Oil and Polyethylene Glycol 4000 To a 2% w/v solution of sodium alginate 10% w/v soya bean oil, 0.5% w/v polyethylene glycol 4000 and 3% w/v Dapsone were added. The resultant mixture was agitated to form an dispersion, which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 3 Encapsulation of Dapsone Soya Bean Oil and Colloidal Silicon Dioxide To a 2% w/v solution of sodium alginate 10% w/v soya bean oil, 0.5% w/v colloidal silicon dioxide and 3% w/v Dapsone were added. The resultant mixture was agitated to form a dispersion, which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 4 Encapsulation of 2-n-octadecylindole-5-carboxylic acid and Gelucire 35/10 To a 2% w/v solution of sodium alginate 3% w/v 2-n-octadecylindole-5-carboxylic acid was added. The suspension was warmed to 40"C to which 5% w/v melted Gelucire 35/10 was added. The resultant mixture was agitated to form a dispersion, which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 5 Encapsulation of 2-n-octadecylindole-5-carboxylic acid and Gelucire 37/02 To a 2% w/v solution of sodium alginate 3% w/v 2-n-octadecylindole-5-carboxylic acid was added. The suspension was warmed to 40"C to which 5% w/v melted Gelucire 37/02 was added. The resultant mixture was agitated to form a dispersion, which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 6 Encapsulation of 2-n-octadecylindole-5-carboxylic acid To a 2% w/v solution of sodium alginate 3% w/v 2-n-octadecylindole-5-carboxylic acid was added. The resultant mixture was agitated to form a dispersion, which was then added dropwise to a 4% w/v calcium lactate solution. The beads were filtered and washed with deionised water, and dried in an oven at 50"C.
Dissolution Profiles of Examples 1-3 The dissolution profile was determined using 500 mg beads. The beads were soaked for 1 hour in 500 ml Artificial Gastric Juice USP prior to dissolution in 500 ml Artificial Intestinal Juice USP at 37"C (rotating baskets, 125 rpm). At each time interval 1 ml samples were taken and diluted to 25 ml with 0.1 N hydrochloric acid. The uv absorption of Dapsone was measured between wavelengths of 270 and 300 nm.
The results are displayed in Figure 1.
Dissolution Profiles of Examples 4-6 The dissolution profile was determined using 500 mg beads. The beads were soaked for 1 hour in 450 ml Artificial Gastric Juice USP (together with 50 ml isopropyl alcohol and 4.5 g Brij 35) prior to dissolution in 450 ml Artificial Intestinal Juice USP (together with 50 ml isopropyl alcohol and 4.5 g Brij 35) at 37"C (rotating baskets, 125 rpm). At each time interval 5 ml samples were taken and diluted to 10 ml with a solution containing 70% v/v methanol, 25% v/v water, 5% v/v ammonia. The uv absorption of 2-n-octadecylindole-5-carboxylic acid was measured at a wavelength of 270 nm.
The results are displayed in Figure 2.
EXAMPLE 7 To a 2% w/w solution of sodium alginate, 2% w/w Ketoprofen B.P. and 6% w/w PEG 400, PEG 4000 or Gelucire 37/02 were added. The resultant mixture was agitated to form a dispersion which was then dropped into 4% w/v calcium lactate solution to form beads. The beads were filtered and washed with deionised water, and dried in an oven at 50"C. The beads containing PEG 400 or PEG 4000 showed a markedly increased dissolution rate compared with those containing Gelucire 37/02 due to the greater hydrophilicity of PEG 400 and PEG 4000.
EXAMPLE 8 To a 2% w/w solution of sodium alginate, 0.5% w/w Chlorpromazine Hydrochloride BP and 7.5% w/w PEG 4000 or Gelucire 37/02 were added. The resultant mixture was agitated to form a dispersion, which was then added dropwise to a solution containing 4% w/v calcium lactate and 0.5% w/v Chlorpromazine Hydrochloride to form beads.
The beads were filtered and washed with deionised water, and dried in an oven at 50"C. The beads containing PEG 4000 showed a markedly increased dissolution rate compared with those containing Gelucire 37/02 due to the greater hydrophilicity of PEG 4000.
EXAMPLE 9 To a 2% w/w solution of sodium alginate, 0.5% w/w Frusemide BP, 0.5% w/w Amiloride BP and 7% w/w PEG 4000 were added.
The resultant mixture was agitated to form a dispersion, which was then added dropwise to a solution containing 4% w/v calcium lactate, 4% w/v calcium chloride or 4% w/v magnesium nitrate. The beads obtained were filtered, washed with deionised water, and dried in an oven at 50"C.
EXAMPLE 10 To a 2% w/v solution of sodium alginate, 1.5% w/w Paracetamol BP, 0.5% w/w Codeine Phosphate BP and 60% w/w PEG 4000 were added. The resultant mixture was agitated to form a dispersion which was then added dropwise to a solution containing 2% w/v calcium lactate and 2% w/v calcium chloride or 4% w/w calcium chloride or 4% w/v calcium lactate. The beads obtained were filtered, washed with deionised water and dried at 50"C.
Gelled alginate comprising pharmaceutical, eg microcapsules or beads, prepared by the process of the invention may be used as such or may be incorporated into known pharmaceutical compositions for administration, eg orally.
The present invention also includes within its scope pharmaceutical formulations which comprise a gelled alginate according to the invention, generally in association with a pharmaceutically acceptable carrier or coating. In clinical practice the formulations of the present invention will generally be administered orally.
Solid compositions for oral administration include compressed tablets and powders. In such solid compositions, the gelled alginate is generally admixed with at least one inert diluent. The compositions may also comprise additional substances other than inert diluents, eg lubricating agents, such as magnesium stearate.
Liquid compositions for oral administration include pharmaceutically acceptable suspensions containing inert diluents commonly used in the art such as water and oils.
Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.
The compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing gelled alginate with or without the addition of extra diluents or excipients.
Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and absorbable organic esters such as ethyl oleate. The compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents.
The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment and the condition of the patient.

Claims (25)

1. A gelled alginate which comprises a pharmaceutical and, as a release-modifying adjuvant, a pharmaceutically acceptable excipient.
2. A gelled alginate according to claim 1 in which the pharmaceutical is hydrophobic and waterinsoluble.
3. A gelled alginate according to claim 1 in which the pharmaceutical is hydrophilic and water-soluble.
4. A gelled alginate according to claim 3 in which the pharmaceutical is chlorpromazine hydrochloride, chloroquine phosphate or trimipramine maleate.
5. A gelled alginate according to claim 1 or 2 in which the pharmaceutical is ketoprofen, dapsone, sulphathiazole, paracetamol or 2-n-octadecylindole-5carboxylic acid.
6. A gelled alginate according to any one of the preceding claims which comprises from 0.1 to 98% w/w of pharmaceutical.
7. A gelled alginate according to any one of the preceding claims which comprises from 5 to 40% w/w of pharmaceutical.
8. A gelled alginate according to any one of the preceding claims which comprises about 20% w/w of pharmaceutical.
9. A gelled alginate according to any one of the preceding claims which comprises from 1 to 98% w/w of alginate.
10. A gelled alginate according to any one of the preceding claims which comprises from 1 to 40% w/w of alginate.
11. A gelled alginate according to any one of the preceding claims which comprises about 20% w/w of alginate.
12. A gelled alginate according to any one of the preceding claims which comprises from 1 to 98% w/w of release-modifying adjuvant.
13. A gelled alginate according to any one of the preceding claims which comprises from 5 to 80% w/w of release-modifying adjuvant.
14. A gelled alginate according to any one of the preceding claims which comprises about 60% w/w of release-modifying adjuvant.
15. A gelled alginate according to any one of the preceding claims in the form of beads.
16. A gelled alginate according to claim 15 in which the beads have a diameter from 50 to 4000ss.
17. A gelled alginate according to claim 15 in which the beads have a diameter from 150 to 1500y.
18. A gelled alginate according to claim 1 substantially as hereinbefore described in any one of Examples 1 to 10.
19. A process for the preparation of a gelled alginate according to claim 1 which comprises (a) contacting a first aqueous composition comprising a watersoluble alginate and a release-modifying adjuvant and, optionally, a pharmaceutical and (b) a second aqueous composition comprising a water-soluble polyvalent metal salt and, optionally, a pharmaceutical, at least one of the first and second compositions comprising pharmaceutical.
20. A process according to claim 19 in which the water-soluble alginate is sodium alginate.
21. A process according to claim 19 or 20 in which the polyvalent metal salt is calcium lactate.
22. A process according to any one of claims 19 to 21 in which the first aqueous composition comprises about 2% w/v of water-soluble alginic acid salt.
23. A process according to any one of claims 19 to 22 in which the second aqueous composition comprises about 4% w/v of polyvalent metal salt.
24. A process according to claim 18 substantially as hereinbefore described in any one of Examples 1 to 10.
25. A pharmaceutical composition which comprises a gelled alginate according to any one of claims 1 to 18.
GB9121219A 1991-10-04 1991-10-04 Gelled alginate compositions Withdrawn GB2260080A (en)

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GB2260080A true GB2260080A (en) 1993-04-07

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Cited By (5)

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GB2279871A (en) * 1993-06-23 1995-01-18 Jevco Ltd Active agent delivery systems
FR2746035A1 (en) * 1996-03-15 1997-09-19 Flamel Tech Sa COMPOSITE GEL MICROPARTICLES LIKELY TO BE USED AS ACTIVE (S) VECTOR (S), ONE OF THEIR PREPARATION METHODS AND THEIR APPLICATIONS
WO1998010746A1 (en) * 1996-09-11 1998-03-19 Virotex Corporation Compositions and methods for topical application of therapeutic agents
WO2001036515A2 (en) * 1999-11-19 2001-05-25 Abbott Laboratories Polymeric compositions and a method of making the same
WO2023194899A1 (en) * 2022-04-04 2023-10-12 S.I.I.T. s.r.l. - SERVIZIO INTERNAZIONALE IMBALLAGGI TERMOSALDANTI Delayed-release granulates of melatonin, combinations comprising melatonin, pharmaceutical compositions and dietary supplements containing them, and their use in the treatment of insomnia and for the reduction of the time required to fall asleep

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2279871A (en) * 1993-06-23 1995-01-18 Jevco Ltd Active agent delivery systems
GB2279871B (en) * 1993-06-23 1997-05-07 Jevco Ltd Drug retention systems for use in aquaculture
FR2746035A1 (en) * 1996-03-15 1997-09-19 Flamel Tech Sa COMPOSITE GEL MICROPARTICLES LIKELY TO BE USED AS ACTIVE (S) VECTOR (S), ONE OF THEIR PREPARATION METHODS AND THEIR APPLICATIONS
WO1997034584A1 (en) * 1996-03-15 1997-09-25 Flamel Technologies Composite gel microparticles as active principle carriers
WO1998010746A1 (en) * 1996-09-11 1998-03-19 Virotex Corporation Compositions and methods for topical application of therapeutic agents
US5863560A (en) * 1996-09-11 1999-01-26 Virotex Corporation Compositions and methods for topical application of therapeutic agents
US6060085A (en) * 1996-09-11 2000-05-09 Osborne; David W. Compositions and methods for topical application of therapeutic agents
US6620435B1 (en) 1996-09-11 2003-09-16 Virotex Corporation Compositions for topical application of therapeutic agents
WO2001036515A2 (en) * 1999-11-19 2001-05-25 Abbott Laboratories Polymeric compositions and a method of making the same
US6503528B1 (en) 1999-11-19 2003-01-07 Abbott Laboratories Polymeric compositions and a method of making the same
WO2001036515A3 (en) * 1999-11-19 2003-03-13 Abbott Lab Polymeric compositions and a method of making the same
WO2023194899A1 (en) * 2022-04-04 2023-10-12 S.I.I.T. s.r.l. - SERVIZIO INTERNAZIONALE IMBALLAGGI TERMOSALDANTI Delayed-release granulates of melatonin, combinations comprising melatonin, pharmaceutical compositions and dietary supplements containing them, and their use in the treatment of insomnia and for the reduction of the time required to fall asleep

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