CA2164100A1 - Pharmaceutical preparations for poorly-soluble active agents - Google Patents
Pharmaceutical preparations for poorly-soluble active agentsInfo
- Publication number
- CA2164100A1 CA2164100A1 CA002164100A CA2164100A CA2164100A1 CA 2164100 A1 CA2164100 A1 CA 2164100A1 CA 002164100 A CA002164100 A CA 002164100A CA 2164100 A CA2164100 A CA 2164100A CA 2164100 A1 CA2164100 A1 CA 2164100A1
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- Prior art keywords
- oil
- fatty acid
- pharmaceutical composition
- component
- mixture
- Prior art date
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Transplantation (AREA)
- Biochemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The present invention relates to pharmaceutical preparations for poorly-soluble active agents, as well as processes for the production of these preparations. The solubilization agents employed are polyglycerol fatty acid esters or sorbitan fatty acid esters in combination with lipophilic excipients and non-ionic surfactants.
Description
ENGLISH TRANSLATION OF THE SPEC. AS ORIGINALLY FILED
21~4100 Pharmaceutical preparations for poorly-soluble active agents The present invention relates to pharmaceutical preparations for poorly-soluble active agents, as well as processes for the production of these preparations.
In general, the delivery of a pharmaceutical active agent by means of oral administration, such as tablets, capsules or dragées, offers advantages over other, e.g. parenteral forms of administration. Purely subjectively, illnesses which have to be treated by injections are regarded as more serious in comparison with other illnesses in which the administration of tablets, capsules or dragées is hardly noticed. What is particularly advantageous is the suitability of such forms for administration by the patient himself, while, apart from a few exceptions, parenteral administration must be applied by the doctor or by a qualified medical assistant.
After administration and disintegration of an oral delivery form, the liquid in the gastrointestinal tract, e.g. gastric or intestinal juice, acts on the active agent. Many active agents for oral application have lipophilic properties, and are therefore poorly soluble in the aqueous environment of the gastro-intestinal tract. In this case, the amount of active agent that is capable of resorption is reduced, so that its bio-availability decreases. In general, this necessitates higher dosaging of the active substance to be applied.- ~onsequences thereof are increased biological variability and undesired variations in efficacy.
In order to improve solubility of poorly-soluble active agents, so-called solubilising agents have been described, e.g. hydrophilic cosolvents such as ethanol, propylene glycol, liquid polyethylene glycols, or lipophilic solubilising agents such as lecithin, fatty acid polyglycol esters or fatty acid glycerol polyglycol esters. When using such 2164~Q
21~4100 Pharmaceutical preparations for poorly-soluble active agents The present invention relates to pharmaceutical preparations for poorly-soluble active agents, as well as processes for the production of these preparations.
In general, the delivery of a pharmaceutical active agent by means of oral administration, such as tablets, capsules or dragées, offers advantages over other, e.g. parenteral forms of administration. Purely subjectively, illnesses which have to be treated by injections are regarded as more serious in comparison with other illnesses in which the administration of tablets, capsules or dragées is hardly noticed. What is particularly advantageous is the suitability of such forms for administration by the patient himself, while, apart from a few exceptions, parenteral administration must be applied by the doctor or by a qualified medical assistant.
After administration and disintegration of an oral delivery form, the liquid in the gastrointestinal tract, e.g. gastric or intestinal juice, acts on the active agent. Many active agents for oral application have lipophilic properties, and are therefore poorly soluble in the aqueous environment of the gastro-intestinal tract. In this case, the amount of active agent that is capable of resorption is reduced, so that its bio-availability decreases. In general, this necessitates higher dosaging of the active substance to be applied.- ~onsequences thereof are increased biological variability and undesired variations in efficacy.
In order to improve solubility of poorly-soluble active agents, so-called solubilising agents have been described, e.g. hydrophilic cosolvents such as ethanol, propylene glycol, liquid polyethylene glycols, or lipophilic solubilising agents such as lecithin, fatty acid polyglycol esters or fatty acid glycerol polyglycol esters. When using such 2164~Q
solubilising agents, problems arise due to decreased tolerance and inadequate stability of the delivery form, e.g. separation effects.
Therefore, in German published specification DOS 40 05 190, it was proposed thatglycerol fatty acid partial esters should be used, or partial esters of propylene glycol. These excipients (co-surfactants) are disadvantageous, since they are only obtainable in the narrow HLB range of 2 to 3. This allows only a limited variation in the proportions of constituents in the carrier composition for the purpose of adapting to the differing solubilities of the active agents to be dissolved.
The present invention is based on the problem of increasing or improving the solubility, resorption capacity and consequently also the bio-availability of active agents for oral application by selecting particularly appropriate excipients.
This problem is solved by the present invention, which relates to a particularlyadvantageous pharmaceutical composition for the improved solubilization of an active agent having poor solubility in water in the carrier composition. The carrier composition according to the present invention comprises the following components:
a) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure co-surfactant, or one which is present as a mixture, with a hydrophilic-lipophilic balance of less than 10 (HLB value according to Griffin), selected from the group of polyglycerol fatty acid esters and sorbitan fatty acid esters;
b) ca. 5-40 % by weight, based on the carrier composition, of an essentially pure pharmaceutically acceptable oil, or one which is present as a mixture, which contains a triglyceride as an essential lipophilic component; and c) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure non-ionic surfactant, or one which is present as a mixture, with an HLB value greaterthan 10;
and optionally further pharmaceutically acceptable excipients.
In addition, the process for the production of a pharmaceutical composition having a solubilized active agent with poor water-solubility, in a carrier composition consisting of the said components, is also an object of the invention. This pharmaceutical composition is suitable for filling into oral unit dosage forms, e.g. in starch-, hard-gelatin or soft-gelatin capsules.
The terms used above and in the following are defined as follows within the scope of the description of the present invention:
The term pharmaceutical composition defines the mixture of a solubilized pharma-ceutical active agent or active agent mixture having poor water-solubility, in acarrier composition consisting of said components, wherein the mixture is adapted for processing into oral delivery forms, preferably starch-, hard-gelatin or soft-gelatin capsules.
The term solubilized, or solubilization of an active agent or active agent mixture having poor water-solubility defines a dispersion procedure which works through the action of an appropriate solubilising agent, whereby this agent increases the dispersion capacity of the active agent to such an extent that a therapeuticallyeffective dosage is completely dissolved or at least becomes bio-available as a result of a partial dissolving process. The term dispersion capacity defines a measure of the formation of micro-emulsions, true molecular solutions of the active agents and excipients in water, as well as colloidal solutions, e.g. solutions of association colloids or molecular colloids, which are clear or opalescent, and where necessary after filtration, especially using sterile filters of ca. 5-10 ,um pore diameter, leave no solid particles of any kind, or e.g. micellar solutions or spherocolloids, which can only be separated in an ultra-centrifuge. The dispersion 21641~0 capacity may be given e.g. in mg or mmols per litre of water.
A pharmaceutical active agent or active agent mixture which is poorly soluble inwater has a solubility in water of less than 500 mg/1000 ml, preferably less than 200 mg/ml.
Especially suitable poorly-soluble active agents are immunosuppressants having macrolide structure, e.g. cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal antiphlogisticagents, e.g. acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin, diclofenac, piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen,fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumeton; dihydropyridine derivatives having cardiovascular activity, e.g.
nifedipine, nitrendipine, nimodipine, nisoldipine, isradipine, felodipine, amlodipine, nilvadipine, lacidipine, benidipine, masnidipine, furnidipine, niguldipine, neuro-therapeutics, e.g. a-lipoic acid, muramyl peptides, e.g. muramyl dipeptide or tripeptide, romurtid, fat-soluble vitamins, e.g. vitamin A, D, E or F; alkaloids, e.g.
vincopectine, vincristine, vinblastine, reserpine, codeine, ergot alkaloids, e.g.
bromocriptine, dihydroergotamine, dihydroergocristine; anti-tumour agents, e.g.
chlorambucil, etoposide, teniposide, idoxifen, tallimustine, teloxantrone, tirapazamine, carzelesine, dexniguldipine, intoplicine, idarubicin, miltefosine,trofosfamide, teloxantrone, melphalan, lomustine, 4,5-bis(4'-fluoranilino)-phthalimide;
4,5-dianilinophthalimide; immuno-modulators, e.g. thymoctonan, prezatide copper acetate; anti-infection agents, e.g. erythromycin, daunorubicin, gramicidin, doxorubicin, amphotericin-B, gentamycin, leucomycin, streptomycin, ganefromycin,rifamexil, ramoplanin, spiramycin; anti-mycotic agents, e.g. fluconazole, ketoconazole, itraconazole; H2-receptor antagonists, e.g. famotidine, cimetidine, ranitidine, roxatidine, nizatidine, omeprazole, protein-kinase inhibitors, e.g. N-[4-methyl-3-(4-pyridine-3-ylpyrimidin-2-ylamino)-phenyl]-benzamide, N-benzoyl-staurosporin; HlV-1-protease inhibitors, e.g. BOC-PheCPhe-Val-Phe-morpholine or its 0-[2-(2-methoxyethoxy)-acetoxy] derivative; leucotriene antagonists, e.g. N-[4-(5-21 ~4100 cyclopentyloxycarbonylamino-1 -methylindol-3-ylmethyl)-3-methoxybenzoyl]-2-vinyloxy]-benzene-sulfonamide .
Those preferred in particular are cyclosporins, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, nifedipine, nimodipine, etoposide, ibuprofen and a-lipoic acid.
Instead of the active agent which is present as the free acid or in basic form, in the pharmaceutical composition the active agent may also be present in the form of apharmaceutically acceptable salt, e.g. as the hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate, sulfate, maleate, etc.
The concentration of active agent, or of active agent combination, is determined by the dosage to be applied. It may be 1 to 30% by weight, preferably 5 to 20% by weight, especially 5 to 12% by weight, based on the weight of the carrier composition .
The carrier composition for one of the listed active agents or for an active agent combination is defined as follows:
The requirement "essentially pure" with reference to a component present in the carrier composition defines a degree of purity of this component greater than 90%, preferably greater than 95%, prior to mixing with the other components in the carrier composition. A component defined as "essentially pure" preferably has a simply defined structure and-composition.
The components present as a mixture in the carrier composition may be mixtures of natural agents, the composition of which is stipulated by the raw material itself, its isolation and its further processing. The constituents of such mixtures are indicated in the specifications given by the manufacturer.
21 641~3 The polyglycerol fatty acid ester of component a) comprises an essentially pure polyglycerol fatty acid ester or mixture of polyglycerol fatty acid esters, wherein the polyglycerol contains preferably up to and including 10 glycerol units, which are esterified with 1-10 acid radicals from saturated or unsaturated carboxylic acids with an even number of 8-20 C-atoms.
The acid radical of a saturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the polyglycerol, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
The acid radical of an unsaturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the polyglycerol, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, and has 1 double bond, e.g. 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl or 9-cis-octadecenoyl.
The names indicated in parenthesis are also customary for the said acid radicals:
In addition, the following names are customary for the said acid radicals: 9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadecenoyl (oleyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-icosanoyl (arachidoyl).- -Suitable polyglycerol fatty acid esters having a simply defined structure are fo rexample (with English names) diglycerol monocaprate, diglyceryl monolaurate, diglycerol diisostearate, diglycerol monoisostearate, diglycerol tetrastearate (poly-glyceryl 2-tetrastearate), triglycerol monooleate (polyglyceryl 3-monooleate), triglycerol monolaurate, triglycerol monostearate (polyglyceryl 3-stearate), triglycerol 21641~0 monoisostearate, hexaglycerol dioleate (polyglycerol 6-dioleate), hexaglycerol distearate (polyglycerol 6-distearate), decaglycerol dioleate (polyglycerol 10-dioleate), decaglycerol tetraoleate (polyglycerol 10-tetraoleate), decaglycerol decaoleate (polyglycerol 10-decaoleate), decaglycerol decastearate (polyglycerol10-decastearate). The CTFA nomenclature is given in parenthesis. These products are obtainable commercially under the trade marks Caprol~ (Trademarks belonging to the company Karlshamns USA Inc., Columbus, Ohio). Exact product names:
CAPROL 2G4S, 3GO, 3GS, 6G20, 6G2S, 10G20, 10G40, 10G100, 10GlOS.
Further products are obtainable under the names DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS, TGLC-ML and TGLC-MISOS from the company Solvay Alkali GmbH, D-3002 Hannover.
The mixture of various polyglycerol fatty acid esters is defined under names such as decaglycerol mono-, di-oleate, polyglycerol ester of mixed fatty acids, polyglycerol ester of fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate, isostearate or ricinolate, and is available commercially under the Wordmarks Triodan~ and Homodan~ (Trademarks belonging to the company Grinsted Products, Grinsted, Denmark), exact product names: TRIODAN 20, 55, R90 and HOMODAN
MO, Radiamuls~ (Trademarks belonging to the company Petrofina (FINA), Brussels, Belgium), exact product name RADIAMULS Poly 2253, under the name CAPROL PGE 860 or ET, or the trade marks Plurol~ (Trademarks belonging to Gattefossé Etablissements, Saint-Priest, France), exact product name PLUROL
Stearique WL 1009 or PLUROL Oleique WL 1173. Further products are available under the names PGLC-C 1010 S, PGLC-C 0810, PGLC-C 1010/S, PGLC-L T
2010, PGLC-LAN 0510/S, PGLC-CT 2010/90, PGLC-ISOS T UE, PGLC-R UE, PGLC-ISOS 0410 from the company Solvay Alkali GmbH, D-3002 Hannover.
The listed polyglycerol fatty acid esters fulfill the stipulations relating to "Description", "RequirementsH and "Tests" given on p. 232 in the Foodchemical Codex FCC lll under "Monographs". The product descriptions published by the listed manufacturers are particularly relevant, with details on data sheets for the 2164~0Q
Therefore, in German published specification DOS 40 05 190, it was proposed thatglycerol fatty acid partial esters should be used, or partial esters of propylene glycol. These excipients (co-surfactants) are disadvantageous, since they are only obtainable in the narrow HLB range of 2 to 3. This allows only a limited variation in the proportions of constituents in the carrier composition for the purpose of adapting to the differing solubilities of the active agents to be dissolved.
The present invention is based on the problem of increasing or improving the solubility, resorption capacity and consequently also the bio-availability of active agents for oral application by selecting particularly appropriate excipients.
This problem is solved by the present invention, which relates to a particularlyadvantageous pharmaceutical composition for the improved solubilization of an active agent having poor solubility in water in the carrier composition. The carrier composition according to the present invention comprises the following components:
a) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure co-surfactant, or one which is present as a mixture, with a hydrophilic-lipophilic balance of less than 10 (HLB value according to Griffin), selected from the group of polyglycerol fatty acid esters and sorbitan fatty acid esters;
b) ca. 5-40 % by weight, based on the carrier composition, of an essentially pure pharmaceutically acceptable oil, or one which is present as a mixture, which contains a triglyceride as an essential lipophilic component; and c) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure non-ionic surfactant, or one which is present as a mixture, with an HLB value greaterthan 10;
and optionally further pharmaceutically acceptable excipients.
In addition, the process for the production of a pharmaceutical composition having a solubilized active agent with poor water-solubility, in a carrier composition consisting of the said components, is also an object of the invention. This pharmaceutical composition is suitable for filling into oral unit dosage forms, e.g. in starch-, hard-gelatin or soft-gelatin capsules.
The terms used above and in the following are defined as follows within the scope of the description of the present invention:
The term pharmaceutical composition defines the mixture of a solubilized pharma-ceutical active agent or active agent mixture having poor water-solubility, in acarrier composition consisting of said components, wherein the mixture is adapted for processing into oral delivery forms, preferably starch-, hard-gelatin or soft-gelatin capsules.
The term solubilized, or solubilization of an active agent or active agent mixture having poor water-solubility defines a dispersion procedure which works through the action of an appropriate solubilising agent, whereby this agent increases the dispersion capacity of the active agent to such an extent that a therapeuticallyeffective dosage is completely dissolved or at least becomes bio-available as a result of a partial dissolving process. The term dispersion capacity defines a measure of the formation of micro-emulsions, true molecular solutions of the active agents and excipients in water, as well as colloidal solutions, e.g. solutions of association colloids or molecular colloids, which are clear or opalescent, and where necessary after filtration, especially using sterile filters of ca. 5-10 ,um pore diameter, leave no solid particles of any kind, or e.g. micellar solutions or spherocolloids, which can only be separated in an ultra-centrifuge. The dispersion 21641~0 capacity may be given e.g. in mg or mmols per litre of water.
A pharmaceutical active agent or active agent mixture which is poorly soluble inwater has a solubility in water of less than 500 mg/1000 ml, preferably less than 200 mg/ml.
Especially suitable poorly-soluble active agents are immunosuppressants having macrolide structure, e.g. cyclosporin A, cyclosporin G, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal antiphlogisticagents, e.g. acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin, diclofenac, piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen,fenoprofen, felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumeton; dihydropyridine derivatives having cardiovascular activity, e.g.
nifedipine, nitrendipine, nimodipine, nisoldipine, isradipine, felodipine, amlodipine, nilvadipine, lacidipine, benidipine, masnidipine, furnidipine, niguldipine, neuro-therapeutics, e.g. a-lipoic acid, muramyl peptides, e.g. muramyl dipeptide or tripeptide, romurtid, fat-soluble vitamins, e.g. vitamin A, D, E or F; alkaloids, e.g.
vincopectine, vincristine, vinblastine, reserpine, codeine, ergot alkaloids, e.g.
bromocriptine, dihydroergotamine, dihydroergocristine; anti-tumour agents, e.g.
chlorambucil, etoposide, teniposide, idoxifen, tallimustine, teloxantrone, tirapazamine, carzelesine, dexniguldipine, intoplicine, idarubicin, miltefosine,trofosfamide, teloxantrone, melphalan, lomustine, 4,5-bis(4'-fluoranilino)-phthalimide;
4,5-dianilinophthalimide; immuno-modulators, e.g. thymoctonan, prezatide copper acetate; anti-infection agents, e.g. erythromycin, daunorubicin, gramicidin, doxorubicin, amphotericin-B, gentamycin, leucomycin, streptomycin, ganefromycin,rifamexil, ramoplanin, spiramycin; anti-mycotic agents, e.g. fluconazole, ketoconazole, itraconazole; H2-receptor antagonists, e.g. famotidine, cimetidine, ranitidine, roxatidine, nizatidine, omeprazole, protein-kinase inhibitors, e.g. N-[4-methyl-3-(4-pyridine-3-ylpyrimidin-2-ylamino)-phenyl]-benzamide, N-benzoyl-staurosporin; HlV-1-protease inhibitors, e.g. BOC-PheCPhe-Val-Phe-morpholine or its 0-[2-(2-methoxyethoxy)-acetoxy] derivative; leucotriene antagonists, e.g. N-[4-(5-21 ~4100 cyclopentyloxycarbonylamino-1 -methylindol-3-ylmethyl)-3-methoxybenzoyl]-2-vinyloxy]-benzene-sulfonamide .
Those preferred in particular are cyclosporins, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, nifedipine, nimodipine, etoposide, ibuprofen and a-lipoic acid.
Instead of the active agent which is present as the free acid or in basic form, in the pharmaceutical composition the active agent may also be present in the form of apharmaceutically acceptable salt, e.g. as the hydrobromide, hydrochloride, mesylate, acetate, succinate, lactate, tartrate, fumarate, sulfate, maleate, etc.
The concentration of active agent, or of active agent combination, is determined by the dosage to be applied. It may be 1 to 30% by weight, preferably 5 to 20% by weight, especially 5 to 12% by weight, based on the weight of the carrier composition .
The carrier composition for one of the listed active agents or for an active agent combination is defined as follows:
The requirement "essentially pure" with reference to a component present in the carrier composition defines a degree of purity of this component greater than 90%, preferably greater than 95%, prior to mixing with the other components in the carrier composition. A component defined as "essentially pure" preferably has a simply defined structure and-composition.
The components present as a mixture in the carrier composition may be mixtures of natural agents, the composition of which is stipulated by the raw material itself, its isolation and its further processing. The constituents of such mixtures are indicated in the specifications given by the manufacturer.
21 641~3 The polyglycerol fatty acid ester of component a) comprises an essentially pure polyglycerol fatty acid ester or mixture of polyglycerol fatty acid esters, wherein the polyglycerol contains preferably up to and including 10 glycerol units, which are esterified with 1-10 acid radicals from saturated or unsaturated carboxylic acids with an even number of 8-20 C-atoms.
The acid radical of a saturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the polyglycerol, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
The acid radical of an unsaturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the polyglycerol, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, and has 1 double bond, e.g. 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl or 9-cis-octadecenoyl.
The names indicated in parenthesis are also customary for the said acid radicals:
In addition, the following names are customary for the said acid radicals: 9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadecenoyl (oleyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-icosanoyl (arachidoyl).- -Suitable polyglycerol fatty acid esters having a simply defined structure are fo rexample (with English names) diglycerol monocaprate, diglyceryl monolaurate, diglycerol diisostearate, diglycerol monoisostearate, diglycerol tetrastearate (poly-glyceryl 2-tetrastearate), triglycerol monooleate (polyglyceryl 3-monooleate), triglycerol monolaurate, triglycerol monostearate (polyglyceryl 3-stearate), triglycerol 21641~0 monoisostearate, hexaglycerol dioleate (polyglycerol 6-dioleate), hexaglycerol distearate (polyglycerol 6-distearate), decaglycerol dioleate (polyglycerol 10-dioleate), decaglycerol tetraoleate (polyglycerol 10-tetraoleate), decaglycerol decaoleate (polyglycerol 10-decaoleate), decaglycerol decastearate (polyglycerol10-decastearate). The CTFA nomenclature is given in parenthesis. These products are obtainable commercially under the trade marks Caprol~ (Trademarks belonging to the company Karlshamns USA Inc., Columbus, Ohio). Exact product names:
CAPROL 2G4S, 3GO, 3GS, 6G20, 6G2S, 10G20, 10G40, 10G100, 10GlOS.
Further products are obtainable under the names DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS, TGLC-ML and TGLC-MISOS from the company Solvay Alkali GmbH, D-3002 Hannover.
The mixture of various polyglycerol fatty acid esters is defined under names such as decaglycerol mono-, di-oleate, polyglycerol ester of mixed fatty acids, polyglycerol ester of fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate, isostearate or ricinolate, and is available commercially under the Wordmarks Triodan~ and Homodan~ (Trademarks belonging to the company Grinsted Products, Grinsted, Denmark), exact product names: TRIODAN 20, 55, R90 and HOMODAN
MO, Radiamuls~ (Trademarks belonging to the company Petrofina (FINA), Brussels, Belgium), exact product name RADIAMULS Poly 2253, under the name CAPROL PGE 860 or ET, or the trade marks Plurol~ (Trademarks belonging to Gattefossé Etablissements, Saint-Priest, France), exact product name PLUROL
Stearique WL 1009 or PLUROL Oleique WL 1173. Further products are available under the names PGLC-C 1010 S, PGLC-C 0810, PGLC-C 1010/S, PGLC-L T
2010, PGLC-LAN 0510/S, PGLC-CT 2010/90, PGLC-ISOS T UE, PGLC-R UE, PGLC-ISOS 0410 from the company Solvay Alkali GmbH, D-3002 Hannover.
The listed polyglycerol fatty acid esters fulfill the stipulations relating to "Description", "RequirementsH and "Tests" given on p. 232 in the Foodchemical Codex FCC lll under "Monographs". The product descriptions published by the listed manufacturers are particularly relevant, with details on data sheets for the 2164~0Q
respective product, especially specifications such as monoester content, dropping point, free glycerol, free fatty acid, iodine number, form, anti-oxidants, HLB value, properties and shelf life.
In particular, the polyglycerol fatty acid esters fulfill the requirements according to number E 475 of the EC food additive regulation (EC guideline 74/329) as well asthe regulation of the U.S. FDA Code 21 CFR 172.854.
The sorbitan fatty acid ester of component a) preferably comprises an essentially pure sorbitan fatty acid ester, or mixture of various sorbitan fatty acid esters, wherein the sorbitan is esterified with 1-3 acid radicals of a saturated or unsaturated, straight-chain carboxylic acid, with an even number of 8-20 C-atoms.
The acid radical of a saturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the sorbitan, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl .
The acid radical of an unsaturated carboxylic acid with an even number of 8-20 C-atoms is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. oleoyl.
Suitable sorbitan fatty acid esters are in particular sorbitan -monolaurate, -mono-palmitate, -monostearate, -tristearate, -monooleate, -sesquioleate and -trioleate.
These products are available commercially under the trade marks Span~
(Trademarks belonging-to-the company Atlas,- Wilmington, USA), exact product names: SPAN 20, 40, 60, 65, 80 and 85, Arlacel~ (Trademarks belonging to the company Atlas), exact product names: ARLACEL 20, 40, 60, 80, 83, 85 and C, Crill~ (Trademarks belonging to the company Croda Chemicals Ltd., Cowick Hall, Snaith Goole, GB), exact product names: CRILL 1, 3 and 4, Dehymuls~
(Trademarks belonging to the company Henkel, Dusseldorf DE), exact product names: DEHYMULS SML, SMO, SMS, SSO, Famodan~ (Trademarks belonging to 21~410a the company Grinsted Products, Grinsted, Denmark), exact product names:
FAMODAN MS and TS, Capmul~ (Trademarks belonging to the company Karlshamns USA Inc., Columbus, Ohio), exact product names: CAPMUL S and O, Radiasurf~ (Trademarks belonging to the company Petrofina (FINA), Brussels, Belgium), exact product names: RADIASURF 7125, 7135, 7145 and 7155.
The sorbitan fatty acid esters and the polyglycerol fatty acid esters fulfill the stipulations given in British Pharmacopeia (special monograph) or Ph.Helv. Vl. The product descriptions published by the listed manufacturers are particularly relevant, with details on data sheets for the respective product, especially specifications such as form, colour, HLB value, viscosity, rising melting point and solubility.
Component a) has an HLB value of less than 10. It is present in the carrier composition in an amount of 10-50% by weight, preferably 15-40% by weight, more preferably 15-20% by weight, based on the total weight of the carrier composition.
Component a) may also comprise product mixtures of the polyglycerol fatty acid esters with one another or product mixtures of the sorbitan fatty acid esters with one another, or product mixtures of the polyglycerol fatty acid esters with the sorbitan fatty acid esters.
A pharmaceutically acceptable oil b) is a triglyceride of natural origin or a synthetic or semi-synthetic, essentially pure triglyceride. Preference is given to a triglyceride of natural origin, wherein the glycerol is esterified by acid radicals of saturated or unsaturated carboxylic acids with an even number of 8-20 C-atoms. Such acid radicals are defined above, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl or oleoyl.
Suitable triglycerides of natural origin are e.g. peanut oil, sesame oil, sunflower oil, olive oil, corn oil, soya oil, castor oil, cottonseed oil, rape oil, thistle oil, grapeseed oil, fish oil or neutral oil.
21641~
In particular, the polyglycerol fatty acid esters fulfill the requirements according to number E 475 of the EC food additive regulation (EC guideline 74/329) as well asthe regulation of the U.S. FDA Code 21 CFR 172.854.
The sorbitan fatty acid ester of component a) preferably comprises an essentially pure sorbitan fatty acid ester, or mixture of various sorbitan fatty acid esters, wherein the sorbitan is esterified with 1-3 acid radicals of a saturated or unsaturated, straight-chain carboxylic acid, with an even number of 8-20 C-atoms.
The acid radical of a saturated carboxylic acid with an even number of 8-20 C-atoms, which esterifies the sorbitan, is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl .
The acid radical of an unsaturated carboxylic acid with an even number of 8-20 C-atoms is preferably straight-chained with 12, 14, 16 and 18 C-atoms, e.g. oleoyl.
Suitable sorbitan fatty acid esters are in particular sorbitan -monolaurate, -mono-palmitate, -monostearate, -tristearate, -monooleate, -sesquioleate and -trioleate.
These products are available commercially under the trade marks Span~
(Trademarks belonging-to-the company Atlas,- Wilmington, USA), exact product names: SPAN 20, 40, 60, 65, 80 and 85, Arlacel~ (Trademarks belonging to the company Atlas), exact product names: ARLACEL 20, 40, 60, 80, 83, 85 and C, Crill~ (Trademarks belonging to the company Croda Chemicals Ltd., Cowick Hall, Snaith Goole, GB), exact product names: CRILL 1, 3 and 4, Dehymuls~
(Trademarks belonging to the company Henkel, Dusseldorf DE), exact product names: DEHYMULS SML, SMO, SMS, SSO, Famodan~ (Trademarks belonging to 21~410a the company Grinsted Products, Grinsted, Denmark), exact product names:
FAMODAN MS and TS, Capmul~ (Trademarks belonging to the company Karlshamns USA Inc., Columbus, Ohio), exact product names: CAPMUL S and O, Radiasurf~ (Trademarks belonging to the company Petrofina (FINA), Brussels, Belgium), exact product names: RADIASURF 7125, 7135, 7145 and 7155.
The sorbitan fatty acid esters and the polyglycerol fatty acid esters fulfill the stipulations given in British Pharmacopeia (special monograph) or Ph.Helv. Vl. The product descriptions published by the listed manufacturers are particularly relevant, with details on data sheets for the respective product, especially specifications such as form, colour, HLB value, viscosity, rising melting point and solubility.
Component a) has an HLB value of less than 10. It is present in the carrier composition in an amount of 10-50% by weight, preferably 15-40% by weight, more preferably 15-20% by weight, based on the total weight of the carrier composition.
Component a) may also comprise product mixtures of the polyglycerol fatty acid esters with one another or product mixtures of the sorbitan fatty acid esters with one another, or product mixtures of the polyglycerol fatty acid esters with the sorbitan fatty acid esters.
A pharmaceutically acceptable oil b) is a triglyceride of natural origin or a synthetic or semi-synthetic, essentially pure triglyceride. Preference is given to a triglyceride of natural origin, wherein the glycerol is esterified by acid radicals of saturated or unsaturated carboxylic acids with an even number of 8-20 C-atoms. Such acid radicals are defined above, e.g. n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl or oleoyl.
Suitable triglycerides of natural origin are e.g. peanut oil, sesame oil, sunflower oil, olive oil, corn oil, soya oil, castor oil, cottonseed oil, rape oil, thistle oil, grapeseed oil, fish oil or neutral oil.
21641~
Component b) is present in the carrier composition in an amount of ca. 5-40% by weight, preferably 10-35% by weight, based on the total weight of the carrier composition. Component b) may also consist of product mixtures of the pharmaceutically acceptable oils.
The non-ionic surfactant of component c) with an HLB value of greater than 10 ispreferably an amphiphilic agent, the hydrophilic constituent of which consists of polyethylene oxide, whereby the average molecular weight of the polyethylene oxide portion is ca. 600-2500, corresponding to 15-60 ethylene oxide units.
Suitable non-ionic surfactants are for example reaction products of natural or hydrogenated castor oil and ethylene oxide. Such products are obtainable e.g.
commercially under the Trademarks Cremophor(g), Niccol~) and Emulgin(g. Suitablenon-ionic surfactants are similarly polyoxyethylene sorbitan fatty acid esters (polysorbates), e.g. POE-(20)-sorbitan monolaurate, POE-(20)-sorbitan monopalmitate, POE-(20)-sorbitan tristearate, POE-(20)-sorbitan monooleate or POE-(20)-sorbitan trioleate, as well as polyoxyethylene fatty acid esters, e.g. POE-(20, 30, 40, 50)-stearate. Such products are obtainable e.g. commercially under the Trademarks Tween(~ and Myrj~.
Component c) is present in the carrier composition in an amount of ca. 10-50% byweight, preferably 20-45% by weight, based on the total weight of the carrier composition. Component c) may also consist of product mixtures of the pharmaceutically acceptable non-ionic surfactants.
Suitable, pharmaceutically acceptable, additional excipients are added to the carrier composition in such an amount that they make up 100% by weight with the quantities of components a), b) and c) as well as the active agent or active agent combination. Additional excipients may be present in the carrier composition in amounts of 0% to ca. 75% by weight. Additional excipients are stipulated by the choice of pharmaceutical delivery form. For liquid delivery forms, such as drops, suspensions or capsule fillings, acceptable pharmaceutically acceptable diluents are added, such as ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, glycerol or water or mixtures thereof.
Furthermore, usual excipients may be added, e.g. preservatives such as benzyl alcohol, ethanol, p-hydroxybenzoic acid ester, sorbic acid, anti-oxidants, e.g.
tocopherols, butylhydroxy-anisole, butylhydroxy-toluene, ascorbic acid, ascorbylpalmitate; stabilizers, e.g. citric acid, tartaric acid, EDTA, flavourings or aromatic agents.
The usual consistency agents are suitable for capsule fillings of gelatin capsules, or softeners to attain a stable gelatin shell. Such excipients are e.g. sorbitol, sorbitan, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, methyl cellulose or colloidal silicon dioxide.
Another aspect of this invention is the process for the production of the pharmaceutical composition defined above, which is characterized in that components a), b) and c) and optionally further pharmaceutically acceptable excipients are mixed together in any order, the pharmaceutical active agent which is poorly soluble in water is dispersed in this mixture, and if desired, the dispersion is brought to a suitable, orally administrable form.
Dispersing of the active agent or the active agent combination may take place after mixing the components a), b) and c), as well as the remaining excipients.
Alternatively, the active-agent or active agent combination may be dispersed in an individùal component or in a mixture of two of the said components, and the remaining components added afterwards. The solubilizing dispersing procedures may be accelerated by heating individual components or mixtures thereof.
Reaction conditions which promote the formation of a colloidally disperse phase are preferred.
In the presence of oxygen-sensitive active agents, the process is effected under a protective gas atmosphere, e.g. under nitrogen, helium or argon. Oxygen that is already present in the liquid components may be removed by applying a reduced pressure, e.g. 50-100 mbar, or by means of treatment with ultrasound. A reactioncontainer having a double wall and stirrer is suitable for the process.
The conversion into an orally administrable delivery form is effected in known manner. To produce liquid oral forms such as drops, suspensions, emulsions etc.,known methods are employed, such as those given in standard publications such as Hagers Handbuch der Pharmazeutischen Praxis or Remington's Pharmaceutical Sciences.
The capsules are preferably two-piece gelatin capsules, which are optionally produced by adding glycerol or sorbitol, and dissolve through the action of gastric juices without any time delay. Alternatively, starch capsules may be used, e.g. the commercial products obtainable under the Trademark Capill~ from the company Capsugel/Warner Lambert. Further excipients and fillers, such as lactose, starch, lubricants, such as starch or magnesium stearate, may be mixed with the capsules.
Soft capsules may additionally contain liquids such as lecithin, fats, oils, paraffin oil or liquid polyethylene glycol. Depending on the dosage, two-piece capsules of sizes 0-4, preferably 0-2, are suitable. The commercial products of the companies Shionogi, Capsugel or Scherer are suitable.
The following examples illustrate the invention without limiting its general scope as defined above. The- active-agents are representative of all active agents mentioned above. Temperatures are given in degrees celsius.
~1~4~Q
Example 1 Method for filling into soft gelatin capsules; amounts given jn mg per finished capsule, soft gelatin capsule format: 22 minims oblong.
1. Cyclosporin A (USP XXII/Pharm.Eur.) 100.0 2. POE-(40)-hydrogenated castor oil 400.0 (CREMOPHOR RH 40, NICCOL HCO 40, SIMULSOL 1293) 3. di/tri/tetraglycerol fatty acid ester 238.0 (FCC/ TRIODAN 20) 4. sesame oil (DAB 10) 160.0 5. alpha-tocopherol (DAB 10) 2.0 6. ethanol (DAB 10) 100.0 Ingredients 2-4 are mixed in a stainless steel boiler with a stirrer whilst heating to 40. Gas is removed from the solution by applying a reduced pressure. Anti-oxidant 5 is added to the clear solution and the active agent Cyclosporin A is then dispersed therein. After adding ethanol, the whole batch is stirred until a clear solution is obtained. After cooling to ca. 20, the solution is filled into soft gelatin capsules. To compensate for evaporation, the batch contains 30-60 mg more ethanol than in the above method.
In addition to the gelatin, the walls of the soft gelatin capsules contain excipients which affect the consistency, e.g. glycerol and/or propylene glycol or sorbitol and/or mannitol. The walls may additionally contain pigments or colourants, e.g. titanium dioxide, iron oxide, quinoline yellow or cochineal red A.
Example 2 Method for filling into hard gelatin capsules or starch capsules; amounts given in kg per batch.
1. Nifedipine (DAB 10) 20.0 2. POE-(20)-sorbitan monooleate 168.0 (polysorbate 20 Pharm.Eur., TWEEN 20) 3. triglycerol mono/dioleate (FCC -CAPROL 3GO) 28.0 4. neutral oil (MIGLYOL 812, CAPTEX 300/400) 84.0 All the components are mixed at 45 in a double-walled boiler of 300 I capacity and stirred until a clear solution is obtained. 300 mg batches of the clear, cooled solution are respectively filled into hard gelatin capsules of size 1, which have been rendered opaque with titanium dioxide / iron oxide.
A sealing band is placed around the filled capsules. Owing to the light sensitivity of the nifedipine, all steps of the process must be carried out whilst excluding daylight.
Example 3 Method for filling into a glass boffle. The formulation is suitable for oral administration as a dropping solution, which is filled into a brown 40 ml dropping bottle. The amounts are given in grams.
1. Nimodipine 3.0 2. POE-(60)-hydrogenated castor oil 15.0 (CREMOPHOR RH 60, NICCOL HCO 60, SIMULSOL 1294) 3. sorbitan monolaurate (BPC 1973, SPAN 20) 8.5 4. sunflower oil (DAP 10) 8.5 5. propylene glycol 5.0 Preparation of the solution is effected analogously to example 2.
Example 4 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 4 minims oblong 1. tacrolimus 10.0 2. POE-(35)-castor oil (CREMOPHOR EL) 72.0 3. sorbitan monooleate (SPAN 80) 72.0 4. neutral oil 32.0 5. alpha-tocopherol 1.0 6. propylene glycol (DAB 10) 5.0 Preparation of the capsules is effected analogously to example 1. Propylene glycol is especially suitable for aiding consistency of the capsule wall.
Example 5 Method for filling into hard gelatin capsules; amounts refer to the filling of a capsule of size 0.
1. alpha-lipoic acid 100.0 2. POE-(40)-stearate (US/NF, MYRJ 52 S) 80.0 3. tetraglycol stearate (FCC, TRIODAN 55) 215.0 4. sesame oil 160.0 5. butylhydroxy anisole 0.5 Preparation of the solution is effected analogously to example 2. Here, the oxygen sensitivity of the lipoic acid should also be taken into consideration.
Example 6 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 6 minims oblong.
1. Rapamycin 20.0 2. POLYSORBAT 80 (TWEEN 80) 150.0 3. sorbitan monooleate 25.0 4. neutral oil 75.0 5. ascorbyl palmitate 0.5 6. benzyl alcohol (DAB 10) 5.0 Preparation is effected analogously to example 1, whereby the benzyl alcohol is added as final component.
Example 7 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule.
1. Etoposide 100.0 2. POE-(40)-hydrogenated castor oil 400.0 3. di-/tri-/tetraglycerol laurate 160.0 (TGLC-laurate T2010 Solvay Alkali GmbH) 4. corn oil 230.0 5. ethanol 100.0 Preparation is effected analogously to example 1.
Example 8 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 9.5 minims oblong 1. S(+)-ibuprofen 100.0 2. POLYSORBAT 60 (TWEEN 60) 210.0 3. hexaglycerol dioleate (CAPROL 6G20) 130.0 4. castor oil (DAB 10) 60.0 Preparation is effected analogously to example 1.
The non-ionic surfactant of component c) with an HLB value of greater than 10 ispreferably an amphiphilic agent, the hydrophilic constituent of which consists of polyethylene oxide, whereby the average molecular weight of the polyethylene oxide portion is ca. 600-2500, corresponding to 15-60 ethylene oxide units.
Suitable non-ionic surfactants are for example reaction products of natural or hydrogenated castor oil and ethylene oxide. Such products are obtainable e.g.
commercially under the Trademarks Cremophor(g), Niccol~) and Emulgin(g. Suitablenon-ionic surfactants are similarly polyoxyethylene sorbitan fatty acid esters (polysorbates), e.g. POE-(20)-sorbitan monolaurate, POE-(20)-sorbitan monopalmitate, POE-(20)-sorbitan tristearate, POE-(20)-sorbitan monooleate or POE-(20)-sorbitan trioleate, as well as polyoxyethylene fatty acid esters, e.g. POE-(20, 30, 40, 50)-stearate. Such products are obtainable e.g. commercially under the Trademarks Tween(~ and Myrj~.
Component c) is present in the carrier composition in an amount of ca. 10-50% byweight, preferably 20-45% by weight, based on the total weight of the carrier composition. Component c) may also consist of product mixtures of the pharmaceutically acceptable non-ionic surfactants.
Suitable, pharmaceutically acceptable, additional excipients are added to the carrier composition in such an amount that they make up 100% by weight with the quantities of components a), b) and c) as well as the active agent or active agent combination. Additional excipients may be present in the carrier composition in amounts of 0% to ca. 75% by weight. Additional excipients are stipulated by the choice of pharmaceutical delivery form. For liquid delivery forms, such as drops, suspensions or capsule fillings, acceptable pharmaceutically acceptable diluents are added, such as ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, glycerol or water or mixtures thereof.
Furthermore, usual excipients may be added, e.g. preservatives such as benzyl alcohol, ethanol, p-hydroxybenzoic acid ester, sorbic acid, anti-oxidants, e.g.
tocopherols, butylhydroxy-anisole, butylhydroxy-toluene, ascorbic acid, ascorbylpalmitate; stabilizers, e.g. citric acid, tartaric acid, EDTA, flavourings or aromatic agents.
The usual consistency agents are suitable for capsule fillings of gelatin capsules, or softeners to attain a stable gelatin shell. Such excipients are e.g. sorbitol, sorbitan, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, methyl cellulose or colloidal silicon dioxide.
Another aspect of this invention is the process for the production of the pharmaceutical composition defined above, which is characterized in that components a), b) and c) and optionally further pharmaceutically acceptable excipients are mixed together in any order, the pharmaceutical active agent which is poorly soluble in water is dispersed in this mixture, and if desired, the dispersion is brought to a suitable, orally administrable form.
Dispersing of the active agent or the active agent combination may take place after mixing the components a), b) and c), as well as the remaining excipients.
Alternatively, the active-agent or active agent combination may be dispersed in an individùal component or in a mixture of two of the said components, and the remaining components added afterwards. The solubilizing dispersing procedures may be accelerated by heating individual components or mixtures thereof.
Reaction conditions which promote the formation of a colloidally disperse phase are preferred.
In the presence of oxygen-sensitive active agents, the process is effected under a protective gas atmosphere, e.g. under nitrogen, helium or argon. Oxygen that is already present in the liquid components may be removed by applying a reduced pressure, e.g. 50-100 mbar, or by means of treatment with ultrasound. A reactioncontainer having a double wall and stirrer is suitable for the process.
The conversion into an orally administrable delivery form is effected in known manner. To produce liquid oral forms such as drops, suspensions, emulsions etc.,known methods are employed, such as those given in standard publications such as Hagers Handbuch der Pharmazeutischen Praxis or Remington's Pharmaceutical Sciences.
The capsules are preferably two-piece gelatin capsules, which are optionally produced by adding glycerol or sorbitol, and dissolve through the action of gastric juices without any time delay. Alternatively, starch capsules may be used, e.g. the commercial products obtainable under the Trademark Capill~ from the company Capsugel/Warner Lambert. Further excipients and fillers, such as lactose, starch, lubricants, such as starch or magnesium stearate, may be mixed with the capsules.
Soft capsules may additionally contain liquids such as lecithin, fats, oils, paraffin oil or liquid polyethylene glycol. Depending on the dosage, two-piece capsules of sizes 0-4, preferably 0-2, are suitable. The commercial products of the companies Shionogi, Capsugel or Scherer are suitable.
The following examples illustrate the invention without limiting its general scope as defined above. The- active-agents are representative of all active agents mentioned above. Temperatures are given in degrees celsius.
~1~4~Q
Example 1 Method for filling into soft gelatin capsules; amounts given jn mg per finished capsule, soft gelatin capsule format: 22 minims oblong.
1. Cyclosporin A (USP XXII/Pharm.Eur.) 100.0 2. POE-(40)-hydrogenated castor oil 400.0 (CREMOPHOR RH 40, NICCOL HCO 40, SIMULSOL 1293) 3. di/tri/tetraglycerol fatty acid ester 238.0 (FCC/ TRIODAN 20) 4. sesame oil (DAB 10) 160.0 5. alpha-tocopherol (DAB 10) 2.0 6. ethanol (DAB 10) 100.0 Ingredients 2-4 are mixed in a stainless steel boiler with a stirrer whilst heating to 40. Gas is removed from the solution by applying a reduced pressure. Anti-oxidant 5 is added to the clear solution and the active agent Cyclosporin A is then dispersed therein. After adding ethanol, the whole batch is stirred until a clear solution is obtained. After cooling to ca. 20, the solution is filled into soft gelatin capsules. To compensate for evaporation, the batch contains 30-60 mg more ethanol than in the above method.
In addition to the gelatin, the walls of the soft gelatin capsules contain excipients which affect the consistency, e.g. glycerol and/or propylene glycol or sorbitol and/or mannitol. The walls may additionally contain pigments or colourants, e.g. titanium dioxide, iron oxide, quinoline yellow or cochineal red A.
Example 2 Method for filling into hard gelatin capsules or starch capsules; amounts given in kg per batch.
1. Nifedipine (DAB 10) 20.0 2. POE-(20)-sorbitan monooleate 168.0 (polysorbate 20 Pharm.Eur., TWEEN 20) 3. triglycerol mono/dioleate (FCC -CAPROL 3GO) 28.0 4. neutral oil (MIGLYOL 812, CAPTEX 300/400) 84.0 All the components are mixed at 45 in a double-walled boiler of 300 I capacity and stirred until a clear solution is obtained. 300 mg batches of the clear, cooled solution are respectively filled into hard gelatin capsules of size 1, which have been rendered opaque with titanium dioxide / iron oxide.
A sealing band is placed around the filled capsules. Owing to the light sensitivity of the nifedipine, all steps of the process must be carried out whilst excluding daylight.
Example 3 Method for filling into a glass boffle. The formulation is suitable for oral administration as a dropping solution, which is filled into a brown 40 ml dropping bottle. The amounts are given in grams.
1. Nimodipine 3.0 2. POE-(60)-hydrogenated castor oil 15.0 (CREMOPHOR RH 60, NICCOL HCO 60, SIMULSOL 1294) 3. sorbitan monolaurate (BPC 1973, SPAN 20) 8.5 4. sunflower oil (DAP 10) 8.5 5. propylene glycol 5.0 Preparation of the solution is effected analogously to example 2.
Example 4 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 4 minims oblong 1. tacrolimus 10.0 2. POE-(35)-castor oil (CREMOPHOR EL) 72.0 3. sorbitan monooleate (SPAN 80) 72.0 4. neutral oil 32.0 5. alpha-tocopherol 1.0 6. propylene glycol (DAB 10) 5.0 Preparation of the capsules is effected analogously to example 1. Propylene glycol is especially suitable for aiding consistency of the capsule wall.
Example 5 Method for filling into hard gelatin capsules; amounts refer to the filling of a capsule of size 0.
1. alpha-lipoic acid 100.0 2. POE-(40)-stearate (US/NF, MYRJ 52 S) 80.0 3. tetraglycol stearate (FCC, TRIODAN 55) 215.0 4. sesame oil 160.0 5. butylhydroxy anisole 0.5 Preparation of the solution is effected analogously to example 2. Here, the oxygen sensitivity of the lipoic acid should also be taken into consideration.
Example 6 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 6 minims oblong.
1. Rapamycin 20.0 2. POLYSORBAT 80 (TWEEN 80) 150.0 3. sorbitan monooleate 25.0 4. neutral oil 75.0 5. ascorbyl palmitate 0.5 6. benzyl alcohol (DAB 10) 5.0 Preparation is effected analogously to example 1, whereby the benzyl alcohol is added as final component.
Example 7 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule.
1. Etoposide 100.0 2. POE-(40)-hydrogenated castor oil 400.0 3. di-/tri-/tetraglycerol laurate 160.0 (TGLC-laurate T2010 Solvay Alkali GmbH) 4. corn oil 230.0 5. ethanol 100.0 Preparation is effected analogously to example 1.
Example 8 Method for filling into soft gelatin capsules; amounts given in mg per finished capsule, soft gelatin capsule format: 9.5 minims oblong 1. S(+)-ibuprofen 100.0 2. POLYSORBAT 60 (TWEEN 60) 210.0 3. hexaglycerol dioleate (CAPROL 6G20) 130.0 4. castor oil (DAB 10) 60.0 Preparation is effected analogously to example 1.
Claims (10)
1. Pharmaceutical composition for the solubilization of a poorly soluble active agent in a carrier composition, characterized in that the carrier composition comprises the components:
a) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure co-surfactant, or one which is present as a mixture, with a hydrophilic-lipophilic equilibrium of less than 10 (HLB value according to Griffin), selected from the group of polyglycerol fatty acid esters and sorbitan fatty acid esters;
b) ca. 5-40 % by weight, based on the carrier composition, of an essentially pure, pharmaceutically acceptable oil, or one which is present as a mixture, which contains a triglyceride as an essential lipophilic component; and c) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure non-ionic surfactant, or one which is present as a mixture, with an HLB value greater than 10;
and optionally further pharmaceutically acceptable excipients.
a) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure co-surfactant, or one which is present as a mixture, with a hydrophilic-lipophilic equilibrium of less than 10 (HLB value according to Griffin), selected from the group of polyglycerol fatty acid esters and sorbitan fatty acid esters;
b) ca. 5-40 % by weight, based on the carrier composition, of an essentially pure, pharmaceutically acceptable oil, or one which is present as a mixture, which contains a triglyceride as an essential lipophilic component; and c) ca. 10-50 % by weight, based on the carrier composition, of an essentially pure non-ionic surfactant, or one which is present as a mixture, with an HLB value greater than 10;
and optionally further pharmaceutically acceptable excipients.
2. Pharmaceutical composition according to claim 1 for the solubilization of ca.1-30% by weight, based on the total weight of the carrier composition, of the active agent having a solubility of less than 500 mg/1000 ml in pure water, wherein theactive agent is a cyclosporin, rapamycin, tacrolimus, deoxyspergualin, mycophenolate-mofetil, nifedipine, nimodipine, etoposide, ibuprofen or .alpha.-lipoic acid.
3. Pharmaceutical composition according to claim 1 or 2, wherein the active agent is Cyclosporin A.
4. Pharmaceutical composition according to one of claims 1 - 3, characterized in that component a) comprises an essentially pure polyglycerol fatty acid ester or a mixture thereof, wherein the polyglycerol contains up to and including 10 glycerol units, which are esterified with 1-10 acid radicals of saturated or unsaturated carboxylic acids with an even number of 8-20 C-atoms.
5. Pharmaceutical composition according to claim 4, characterized in that component a) comprises as polyglycerol fatty acid ester an essentially pure poly-glyceryl-2-tetrastearate, -3-monooleate, -3-stearate, -6-dioleate, -6-distearate, -10-dioleate, -10-tetraoleate, -10-decaoleate or -10-decastearate or mixtures thereof.
6. Pharmaceutical composition according to one of claims 1 - 3, characterized in that component a) comprises an essentially pure sorbitan fatty acid ester, or the mixture thereof, wherein the sorbitan is esterified with 1-3 acid radicals of saturated or unsaturated carboxylic acids, with an even number of 8-20 C-atoms.
7. Pharmaceutical composition according to claim 6, characterized in that component a) comprises as the sorbitan fatty acid ester an essentially pure sorbitan monolaurate, monopalmitate, monostearate, tristearate, monooleate, sesquioleate or trioleate or mixtures of these compounds.
8. Pharmaceutical composition according to one of claims 1 - 7, characterized in that component b) comprises as the pharmaceutically acceptable oil peanut oil, sesame oil, sunflower oil, olive oil, corn oil, soya oil, castor oil, cottonseed oil, rape oil, thistle oil, grapeseed oil, fish oil or neutral oil and component c) contains a non-ionic surfactant with a hydrophilic constituent consisting of 15-60 ethylene oxide units.
9. Process for the production of a pharmaceutical composition according to claim 1, characterized in that components a), b) and c) and optionally further pharmaceutically acceptable, water-soluble excipients are mixed together in any order, the pharmaceutical active agent which is poorly soluble in water is dispersed in this mixture, and if desired, the dispersion is brought to a suitable, orallyadministrable form.
10. Process according to claim 9, characterized in that the dispersion is filled into starch-, hard-gelatin or soft-gelatin capsules.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4322826A DE4322826A1 (en) | 1993-07-08 | 1993-07-08 | Pharmaceutical preparation |
| DEP4322826.7 | 1993-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2164100A1 true CA2164100A1 (en) | 1995-01-19 |
Family
ID=6492300
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166204A Expired - Fee Related CA2166204C (en) | 1993-07-08 | 1994-07-08 | Pharmaceutical compositions for sparingly soluble therapeutic agents |
| CA002164100A Abandoned CA2164100A1 (en) | 1993-07-08 | 1994-07-08 | Pharmaceutical preparations for poorly-soluble active agents |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002166204A Expired - Fee Related CA2166204C (en) | 1993-07-08 | 1994-07-08 | Pharmaceutical compositions for sparingly soluble therapeutic agents |
Country Status (24)
| Country | Link |
|---|---|
| EP (3) | EP0710103B1 (en) |
| JP (4) | JPH08512301A (en) |
| KR (2) | KR100386533B1 (en) |
| CN (2) | CN1313154C (en) |
| AT (3) | ATE261720T1 (en) |
| AU (2) | AU689486B2 (en) |
| BR (1) | BR9407002A (en) |
| CA (2) | CA2166204C (en) |
| CY (2) | CY2308B1 (en) |
| CZ (1) | CZ291401B6 (en) |
| DE (6) | DE4322826A1 (en) |
| DK (3) | DK1092429T3 (en) |
| ES (3) | ES2124420T3 (en) |
| FI (2) | FI116197B (en) |
| GR (1) | GR3036571T3 (en) |
| HU (2) | HU228127B1 (en) |
| NO (2) | NO306763B1 (en) |
| NZ (2) | NZ269808A (en) |
| PL (1) | PL179717B1 (en) |
| PT (2) | PT1092429E (en) |
| RU (1) | RU2140291C1 (en) |
| SI (1) | SI1092429T1 (en) |
| SK (1) | SK280615B6 (en) |
| WO (2) | WO1995001786A1 (en) |
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| US8568748B2 (en) | 2001-12-14 | 2013-10-29 | Jagotec Ag | Pharmaceutical formulation comprising cyclosporin and use thereof |
| US8920820B2 (en) | 2001-12-12 | 2014-12-30 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions for needleless injection |
| US8992980B2 (en) | 2002-10-25 | 2015-03-31 | Boehringer Ingelheim Vetmedica Gmbh | Water-soluble meloxicam granules |
| US9101529B2 (en) | 2009-10-12 | 2015-08-11 | Boehringer Ingelheim Vetmedica Gmbh | Containers for compositions comprising meloxicam |
| US9149480B2 (en) | 2010-03-03 | 2015-10-06 | Boehringer Ingeleheim Vetmedica GmbH | Use of meloxicam for the long-term treatment of musculoskeletal disorders in cats |
| US9795568B2 (en) | 2010-05-05 | 2017-10-24 | Boehringer Ingelheim Vetmedica Gmbh | Low concentration meloxicam tablets |
| US9956288B2 (en) | 2000-06-20 | 2018-05-01 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions |
| US10548901B2 (en) | 2004-02-23 | 2020-02-04 | Boehringer Ingelheim Vetmedica Gmbh | Meloxicam for the treatment of respiratory diseases in pigs |
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| GB9409778D0 (en) | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
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| US5597582A (en) * | 1995-09-12 | 1997-01-28 | Sanofi | Oral gel capsule formulation of 1,2,4-benzotriazine oxides |
| DE19549852B4 (en) * | 1995-11-29 | 2009-06-04 | Novartis Ag | Cyclosporin containing preparations |
| CZ288631B6 (en) * | 1996-01-18 | 2001-08-15 | Galena, A. S. | Therapeutic preparations containing cyclosporin |
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1993
- 1993-07-08 DE DE4322826A patent/DE4322826A1/en not_active Withdrawn
-
1994
- 1994-07-08 SI SI9430465T patent/SI1092429T1/en unknown
- 1994-07-08 DE DE59410365T patent/DE59410365D1/en not_active Expired - Lifetime
- 1994-07-08 CZ CZ199645A patent/CZ291401B6/en not_active IP Right Cessation
- 1994-07-08 WO PCT/EP1994/002248 patent/WO1995001786A1/en active IP Right Grant
- 1994-07-08 CN CNB031522890A patent/CN1313154C/en not_active Expired - Lifetime
- 1994-07-08 DK DK00122248T patent/DK1092429T3/en active
- 1994-07-08 KR KR1019960700026A patent/KR100386533B1/en not_active IP Right Cessation
- 1994-07-08 DE DE4494850T patent/DE4494850D2/en not_active Expired - Fee Related
- 1994-07-08 NZ NZ269808A patent/NZ269808A/en not_active IP Right Cessation
- 1994-07-08 PT PT00122248T patent/PT1092429E/en unknown
- 1994-07-08 HU HU9503965A patent/HU228127B1/en not_active IP Right Cessation
- 1994-07-08 PL PL94312255A patent/PL179717B1/en unknown
- 1994-07-08 AT AT00122248T patent/ATE261720T1/en active
- 1994-07-08 EP EP94922269A patent/EP0710103B1/en not_active Expired - Lifetime
- 1994-07-08 JP JP7503830A patent/JPH08512301A/en active Pending
- 1994-07-08 CN CN94192714A patent/CN1121853C/en not_active Expired - Lifetime
- 1994-07-08 PT PT94922269T patent/PT710103E/en unknown
- 1994-07-08 ES ES94923715T patent/ES2124420T3/en not_active Expired - Lifetime
- 1994-07-08 AU AU73457/94A patent/AU689486B2/en not_active Expired
- 1994-07-08 BR BR9407002A patent/BR9407002A/en not_active Application Discontinuation
- 1994-07-08 DE DE59409787T patent/DE59409787D1/en not_active Expired - Lifetime
- 1994-07-08 CA CA002166204A patent/CA2166204C/en not_active Expired - Fee Related
- 1994-07-08 ES ES94922269T patent/ES2159564T3/en not_active Expired - Lifetime
- 1994-07-08 DE DE59407239T patent/DE59407239D1/en not_active Expired - Fee Related
- 1994-07-08 KR KR1019960700042A patent/KR100359044B1/en not_active IP Right Cessation
- 1994-07-08 DE DE4494851T patent/DE4494851D2/en not_active Expired - Fee Related
- 1994-07-08 WO PCT/EP1994/002238 patent/WO1995001785A1/en active IP Right Grant
- 1994-07-08 ES ES00122248T patent/ES2218046T3/en not_active Expired - Lifetime
- 1994-07-08 HU HU9503868A patent/HU223073B1/en active IP Right Grant
- 1994-07-08 RU RU96102012A patent/RU2140291C1/en active
- 1994-07-08 EP EP94923715A patent/EP0710104B1/en not_active Expired - Lifetime
- 1994-07-08 DK DK94923715T patent/DK0710104T3/en active
- 1994-07-08 NZ NZ269552A patent/NZ269552A/en not_active IP Right Cessation
- 1994-07-08 CA CA002164100A patent/CA2164100A1/en not_active Abandoned
- 1994-07-08 SK SK19-96A patent/SK280615B6/en not_active IP Right Cessation
- 1994-07-08 AT AT94923715T patent/ATE172876T1/en not_active IP Right Cessation
- 1994-07-08 EP EP00122248A patent/EP1092429B1/en not_active Expired - Lifetime
- 1994-07-08 DK DK94922269T patent/DK0710103T3/en active
- 1994-07-08 AT AT94922269T patent/ATE201985T1/en active
- 1994-07-08 JP JP7503833A patent/JPH08512303A/en active Pending
- 1994-07-08 AU AU73850/94A patent/AU7385094A/en not_active Abandoned
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1996
- 1996-01-03 FI FI960032A patent/FI116197B/en active IP Right Grant
- 1996-01-04 FI FI960042A patent/FI116714B/en not_active IP Right Cessation
- 1996-01-05 NO NO960069A patent/NO306763B1/en not_active IP Right Cessation
- 1996-01-05 NO NO960062A patent/NO306929B1/en not_active IP Right Cessation
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2001
- 2001-09-10 GR GR20010401428T patent/GR3036571T3/en unknown
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2002
- 2002-12-12 CY CY0200068A patent/CY2308B1/en unknown
-
2005
- 2005-09-08 CY CY0500049A patent/CY2604B2/en unknown
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2009
- 2009-02-04 JP JP2009023837A patent/JP2009138008A/en not_active Withdrawn
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| US6599535B2 (en) | 1995-07-14 | 2003-07-29 | Novartis Ag | Pharmaceutical compositions |
| US6956043B2 (en) | 1995-07-14 | 2005-10-18 | Novartis Ag | Pharmaceutical compositions comprising 33-epi-chloro-33-desoxy-ascomycin solid dispersions |
| US6197781B1 (en) | 1995-07-14 | 2001-03-06 | Novartis Ag | Pharmaceutical compositions |
| US9956288B2 (en) | 2000-06-20 | 2018-05-01 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions |
| US9993557B2 (en) | 2000-06-20 | 2018-06-12 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions |
| US8920820B2 (en) | 2001-12-12 | 2014-12-30 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions for needleless injection |
| US10098891B2 (en) | 2001-12-12 | 2018-10-16 | Boehringer Ingelheim Vetmedica Gmbh | Highly concentrated stable meloxicam solutions for needleless injection |
| US8568748B2 (en) | 2001-12-14 | 2013-10-29 | Jagotec Ag | Pharmaceutical formulation comprising cyclosporin and use thereof |
| US9066955B2 (en) | 2002-10-25 | 2015-06-30 | Boehringer Ingelheim Vetmedica Gmbh | Water-soluble meloxicam granules |
| US8992980B2 (en) | 2002-10-25 | 2015-03-31 | Boehringer Ingelheim Vetmedica Gmbh | Water-soluble meloxicam granules |
| US10548901B2 (en) | 2004-02-23 | 2020-02-04 | Boehringer Ingelheim Vetmedica Gmbh | Meloxicam for the treatment of respiratory diseases in pigs |
| US9101529B2 (en) | 2009-10-12 | 2015-08-11 | Boehringer Ingelheim Vetmedica Gmbh | Containers for compositions comprising meloxicam |
| US9186296B2 (en) | 2009-10-12 | 2015-11-17 | Boehringer Ingelheim Vetmedica Gmbh | Containers for compositions comprising meloxicam |
| US9149480B2 (en) | 2010-03-03 | 2015-10-06 | Boehringer Ingeleheim Vetmedica GmbH | Use of meloxicam for the long-term treatment of musculoskeletal disorders in cats |
| US9795568B2 (en) | 2010-05-05 | 2017-10-24 | Boehringer Ingelheim Vetmedica Gmbh | Low concentration meloxicam tablets |
| US9943486B2 (en) | 2010-05-05 | 2018-04-17 | Boehringer Ingelheim Vetmedica Gmbh | Low concentration meloxicam tablets |
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