GB2201089A - Parenteral suspensions of diclofenac - Google Patents
Parenteral suspensions of diclofenac Download PDFInfo
- Publication number
- GB2201089A GB2201089A GB08801737A GB8801737A GB2201089A GB 2201089 A GB2201089 A GB 2201089A GB 08801737 A GB08801737 A GB 08801737A GB 8801737 A GB8801737 A GB 8801737A GB 2201089 A GB2201089 A GB 2201089A
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- GB
- United Kingdom
- Prior art keywords
- diclofenac
- dry formulation
- salt
- formulation according
- micronised
- 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.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Blow-Moulding Or Thermoforming Of Plastics Or The Like (AREA)
Description
t, t f' h201089 4-163141= Parenteral suspensions The present invention
relates to a dry formulation. in particular a dry formulation obtainable by lyophilisation, which can be used for the preparation of an aqueous stable suspension for the parenteral administration of a diclofenac salt, to the use of said formulation for the preparation of a stable aqueous suspension containing said diclofenac salt, and to the use of this suspension in a therapeutic method of treating the human body.
Various medicaments of different structure are available for the treatment of inflammatory diseases, e.g. rheumatism. As the course inflammations take is often chronic, it is usually necessary to carry out the treatment with antiinflammatory drugs over a prolonged period uf time without interruption. In particular, many nonsteroidal antiinflaminatory drugs (NAIDS), when administered orally, can cause disorders in the entire gastrointestinal tract, especially gastric ulcers.
The sodium salt of diclofenac, available under the registered trademark VoltarenO (Ciba-Geigy), belongs to the group of nonsteroidal antiinflammatory drugs of the first importance.
To enhance drug safety, there is a need to provide novel parenteral dosage forms for diclofenac and the salts ther eof which, compared with the parenteral.injection solutions of the known prior art disclosed e.g. in German Offenlegungsschrift 2 914 788 and European patent application 185 374, have the advantage of a very rapid onset of action with long- lasting therapeutic effects.
Suspensions of diclofenac or diclofenac sodium for parenteral, in particular intramuscular, administration are disclosed in US patent specification 4 614 741. Fatty oils such as sesame oil, olive oil and the like, are used as suspending media for these suspensions. Quite generally, the use of fatty oils as adjuvants for parenteral dosage forms is inexpedient, as they increase the viscosity of the dosage form, thereby causing pain when it is administered (q.v. R. Voigt, Lehrbuch der Pharmazeutischen Technologie, Verlag Chemie, p. 383, 19.5.1.2.1). Consequently, there is also a need for suspensions containing a diclofenac salt, in particular diclofenac sodium, for substantially pain- free intramuscular administration.
The above objects of the invention are achieved by means of the present invention, which relates to a dry formulation containing a diclofenac salt in micronised form without deleterious adjuvants. This dry formulation, after being suspended in an aqueous liquid vehicle, is converted into a dosage form for parenteral administration.
Accordingly, the present invention relates to a dry formulation, in particular a dry formulation obtainable by lyophilisation, which can be used for the preparation of a stable aqueous suspension for the parenteral administration of a diclofenac salt. The dry formulation contains a pharmaceutically acceptable and micronised salt of diclofenac. and optional pharmaceutically acceptable adjuvants.
A pharmaceutically acceptable salt of diclofenac, o-(2,6dichloroanilino)phenylacetic acid, is in particular an alkali metal salt, e.g. the sodium or potassium salt, or a salt with an amine, e.g. a mono-, di- or trialkylamine containing 1 to 4 carbon atoms in the alkyl moiety or moieties, e.g. diethylamine or triethylamine, hydroxyalkylamine contain-Lng 2 to 4 carbon atoms in the alkyl moiety, e.g. ethanolamine, hydroxyalkylalkylamine containing 2 to 4 9 1 1 4.1 4 411 and 1 to 4 carbon atoms respectively In each of the alkyl moieties, e.g. dimethylethanolamine, or a quaternary ammonium salt, e.g. the tetramethylammonium salt or choline salt of diclofenac.
Particularly preferred salts of diclofenac are the sodium and potassium salts (q.v. Merck Index, Tenth Edition, No. 3066).
The dry formulation of this invention contains the diclofenac salt, in particular the sodium or potassium salt of diclofenac, in micronised.form.
The micronised diclofenac salt has a preferred average particle s3.ze smaller than 50)Lm, preferably smaller than 20)im. Particles of this size are obtained by conventional comminution methods, e.g. grinding in an air jet mill, ball mill or vibrator mill. Micronisation is preferably effected by per se known methods using an ultrasonics disintegrator, e.g. of the Branson Sonifier type as described e.g. in J. Pharm. Sci. 53 (9), 1040-1045 (1965), or by stirring a suspension with a high-speed agitator, for example with a stirrer of the Homorex type (supplied by Brogli & Co., Basel). In these preferred methods, micronisation is effected at ca. 500 to 10,000 rpm by dissolving the appropriate salt of diclofenac in an organic solvent, e.g. methanol, ethanol or propylene glycol, and precipitating it in microcrystalline form at ca. 0-5C in water or an aqueous salt solution, e.g. 2 T. sodium chloride solution which may additionally contain a protective colloid such as gelatin or a cellulose ether, e.g. methyl cellulose or hydroxypropyl methyl cellulose, in low concentration (0.1-1 %), and filtering the resultant stirred suspension. The filter cake is dried at low temperature, e.g. ca. 0-5"C, under vacuum (e.g. below 50 mbar, pref,.;rably at 0.5 mbar). The subsequent drying can be effected at ca. 50-90C.
Pharmaceutically acceptable adjuvants which the dry formulation may contain are e.g. ionic isotonic components such as sodium chloride, or nonionic components, especially builders, such as sorbitol, mannitol or glucose. Preferably the dry formulation contains these adjuvants, e.g. sodium chloride or mannitol, in the prescribed amounts which are necessary for establishing the isotonic conditions of the suspension.
Further adjuvants present in low concentration are e.g. emulsifiers which may be used as wetting agents, e.g. phospholipids, e.g. phosphatidyl choline (lecithln), phosphatidyl ethanolamine (cephalin), phopphatidyl serine, phosphatidyl linositol or mixtures of these lipids.
Preferred phospholipids are, for example, soybean or egg lecithin, or soybean or egg cephalin in pharmaceutical purity, or mixtures of phospholipids of different pho:phatidyl choline content approved for pharmaceutical use, e.g. mixtures of lecithins which are commercially available under the registered trademarks EpikuronO 145, 170 or 200 (Lucas Meyer, Hamburg) or LipoidO 45.,.80 or 100 (Lipoid KG, Mannheim).
The cited phospholipids may be present in the solid formulation in weight ratios of active drug to phospholipid of 1:0A to 1:1, preferably from 1:0. 1 to 1:1.
Further suitable adjuvants in the dry formulation are wetting agents useful for liquid pharmaceutical formulations or true surfactants, in particular nonionic surfactants of the fatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate, monooleate, monostearate or monopalmitatle, sorbitan tristearate or trioleate, adducts of polyoxethylene and fatty acid polyhydroxy alcohol esters such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monopalmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, in particular ethylene oxide/propylene oxide block polymers of the PluronicsO type (Wyandotte) or SynperonicO (ICI).
t W -j r 4 1 These surfactants may be present in the dry formulation in weight ratios of active drug to surfactant of 1:1.0 X 10-4 to 1:0.1, preferably of 1:0. 03 to 1:0.1.
The dry formulation of this invention is prepared by suspending the amount of-diclofenac salt intended for parenteral administration, in microniSed form, in a suspending medium that contains the optional pharmaceutically acceptable adjuvants, and removing the solvent.
If the dry formulation contains water-Soluble components or adjuvants, such as sodium chloride, mannitol or glucose, which are necessary e.g. for establishing isotonic conditions, then an aqueous suspending medium is preferred. After dissolving the adjuvants in water purified for injection, the aqueous solution is preferably filtered and sterilised or filtered under sterile conditions. To this sterilised solution is then added the micronised diclofenac salt. The preparation of the dry formulation can be effected by known methods of lyophilisation, e.g. normally by filling a specific amount of the prepared suspension into suitable containers such as ampoules, e.g. vials, and thereafter freezing the filled vials at ca. -40' to -50C, preferably at -45'C, and then carrying out lyophilisation under a pressure of ca. 0.05 to 0.6 mbar by slowly warming to a final temperature of ca. 25-55'C.
If the dry formulation contains an adjuvant or component which is.poorly soluble in.water, e.g. a phospholipid such as lecithin, then said adjuvant is dissolved e.g. in a purified organic solvent such as tert- butanol, methanol, ethanol or methylene chloride, and the micronised salt is suspended in this solution. After stripping off the organic solvent, the dry formulation coated with the adjuvant, such as a phospholipid, is filled in powder form into suitable containers, e.g. vials.
Surprisingly, by means of the process of this invention it is possible to prepare dry formulations, especially lyophlllsed formulations, and suspensions that can be reconstituted therefrom and which are stable and suitable for injection.
The use of the dry formulations obtainable by the process of this invention for the preparation of injection suspensions is also an object of this invention. These injection suspensions can be administered as injection formulations parenterally, preferably intramuscularly.
The dry formulation of this invention is reconstituted, prior to administration, as a suspension in the prescribed amount of liquid, especially sterilised (pyrogen-free) water for injection.
A homogeneous suspension of the previously micronised drug is formed once more by shaking. Instead of a dry formulation containing the diclofenac salt and the water-soluble adjuvants such as sodium chloride or mannitol, it is also possible to suspend a dry formulation containing only the diclofenac salt (without adjuvants) in the prescribed,amount of liquid containing the cited water-soluble adjuvants. - The particle size of the micronised drug remains unchanged during the preparation of the suspension. Thus no noticeable crystal growth, e.g. resulting from hydrate formation, is observed in the suspension to be administered. The suspension of the drug also has the advantage that it does not adhere to the wall of the ampoule and can be readily and completely withdrawn from the ampoule with the syringe. A particularly preferred embodiment of the invention comprises preparing injection suspensions that contain the customary doses of 50, 75 or 100 mg of diclofenac sodium, having a total volume of 1.0 to 3.0 ml, preferably of 2.0-1.0 ml, especially a volume of 1.0 ml.
These suspensions can be used as ready for use formulations.
t t M The present invention relates in particular to dry formulations and to the use thereof for the preparation of an aqueous suspension for the intramuscular administration of diclofenac sodium. The dry formulation and the suspension preferably contain micronised diclofenac sodium having an average particle size smaller than 20 JLm and optional adjuvants such as sodium chloride, mannitol, sorbitol as well as lipids such as lecithin or wetting agents of the SYNPERONICO or PLURONICO type4 - The suspensions of this invention can be used for parenteral (intramuscular) formulations for the treatment of painful conditions, inflammations and/orreumatic diseases in warm-blooded animals (human and animals). Daily doses of ca. 25 to 200 mg of active drug can be administered, while the individual dosage form contains the customary amounts of drug of e.g. 25, 50, 75, 100 or 150 mg.
The following Examples illustrate the invention, but imply no restriction to what is described therein.
Example 1: a) Preparation of the lyophilised drug formulation Composition of each ampoule: diclofenac sodium NaCl mg 18 mg Preparation of 10 ampoules: 180 mg of sodium chloride (puriss.) are dissolved in 10 ml of distilled water and the solution is filtered through a membrane filter (pore size: 0.2 1JM) and sterilised, e.g. in an autoclave at ca. 120C.'The sterilised sodium chloride solution is cooled to 5C. To the cooled solution are added 750 mg of micronised diclofenac sodium (puriss.) having an average particle size smaller than 20 Jim and. the resultant suspension is deagglomerated, e.g. in a piston homogeniser or ultrasonics disintegrator. The crystalline suspension is filled at 5'C into 10 sterilised vials of 1.0 ml volume. The vials are frozen at -45% lyophilised in a freeze drying apparatus and then sealed.
b) PreparatioLl of the active drug suspension for parenteral administration (reconstitution) To the contents of a vial containing 75 mg of Iyophilised diclofenac sodium (preparation as described in a) above) are added, at room temperature, 2.0 ml of sterilised water for injection and the lyophilised drug is suspended by shaking. The suspension is withdrawn from the vial with a sterilised syringe and can be administered intramuscularly.
Example 2: a) Following the procedure of Example la), it is possible to prepare lyophilised drug formulations containing 75 mg of diclofenac sodium and 100 mg of mannitol and 9 mg of NaCl. Alternatively, these lyophilised formulations may also additionall-Y contain 0.01 to 10 mg of SynperonicID.
b) Following the procedure of Example lb), it is possible to suspend, at r,,om temperature, lyophilised drug formulations containing 75 mg. of diclofenac sodium in 2.0 ml of sterilised water for injection which contains 0.9 % of NaCl. or lyophilised drug formulations containing 75 mg of diclofenac sodium and 100 mg of mannitol, or 75 mg of diclofenac sodium, 50 mg of mannitol and 9 mg of NaCl in 2.0 ml of sterilised water for injection. Alternatively, these lyophilised drug formulations can also be suspended with the addition of 0.01 to 10 mg of SynperonicO. The isotonic suspensions so obtained can be withdrawn by a sterilised syringe and administered intramuscularly.
1 ts k Example 3:
a) Preparation of the dry formulation (powder) Composition of each ampoule:
diclofenac 75 mg lecithin (EpikuronO 145, 170 or 200) 2-20 mg 1 Preparation of 10 ampoules: The lecithin is dissolved in 10 ml of methylene chloride and the solution is filtered through a membrane (pore size: 0.2 lim). To the filtered solution are-added 750 mg of micronised diclofenac sodium having an average particle size smaller than 20 lim, and the suspension so obtained is deagglomerated (q.v. Example la). The solvent Is then removed under vacuum. The diclofenac sodium powder coated with lecithin is filled into vials such that each contains 75 mg of diclofenac sodium.
b) Preparation of the active drug suspension for parenteral administration Following the procedure of Example la), the contents of a vial containing 75 mg of diclofenac sodium in the form of the lecithincoated powder are suspended at room temperature in 2.0 ml of sterilised water for injection which contains 0.9 % of NaCl or in 2. 0 ml of sterilised water which contains an isotonic mixture of NaCl and mannitol.
Example 4: a) Preparation of the lyophilised drug formulation Composition of each ampoule: diclofenac sodium NaCl mannitol PLURONIC mg 5. 4 mg 20 mg 0.07 ng - 10 Preparation of 10 ampoules: 54.0 mg of sodium chloride (puriss.), 200 mg mannitol and 0.7 mg PLURONIC are dissolved in 7.0 ml of distilled water and the solution is filtered through a membrane filter (pore size: 0.2 lim) and sterilised, e.g. in an autoclave at ca. 120C. The sterilised suspending agent is cooled to 5C. To the cooled solution are added 750 mg of micronised diclofenac sodium (puriss.) having an average particle size smaller than 20 lim and the resultant suspension is deagglomerated, e.g. in a piston homogeniser or ultrasonics disintegrator. The crystalline suspension is filled at 5C into 10 sterilised vials of a volume suitable for 0.8 g substance. The vials are frozen at -45% lyophilised in a freeze drying apparatus and then s-ealed.
1 b) Preparation of the active drug suspension for parenteral administration (reconstitution) To the contents of a vial containing 75 mg of lyophilised diclofenac sodium (preparation as described in a) above) are added, at room temperature, 1.0 ml of sterilised water for injection and the lyophilised drug is suspended by shaking. The suspension is withdrawn from the vial with a sterilised syringe and can be administered intramuscularly.
-- 11 -
Claims (11)
1. A dry formulation for the preparation of a stable, aqueous suspension of diclofenac in salt form, which formulation contains a pharmac eutically acceptable and micronised salt of diclofenac and optional pharmaceutically acceptable.adjuvants.
2. A dry formulation according to claim 1 obtainable by lyophilisation.
3. A dry formulation according.to either claim 1 or claim 2, which contains a diclofenac salt having.an average particle size smaller than 50 ym.
-
4. A dry formulation according to claim 3, which contains a diclofenacsalt having an average particle size smaller than 20 lim.
5. A dry formulation according.to claim.3. which contains diclofenac sodium havingan average particle size smaller than 20 gm.
6. A process for the preparation of a dry formulation according to any one of claims 1 to 4, which comprises suspending a diclofenac salt.in micronised form in a suspending medium which contains theoptional pharmaceutically acceptable adjuvants, and removing said suspending medium.
7. A process according to claim 6, which comprises suspending the diclofenac salt in micronised form in an aqueous suspending medium which contains isotonic components and removing the water.
8. A process according.to claim 6,. which zomprises suspending.the diclofenac salt in micronised form in an organic suspending medium which contains phospholipids and removing the solvent.
9. Use of a dry formulation according to any one of claims I to 5 for the preparation of an aqueous suspension for parenteral administration which contains a pharmaceutically acceptable and micronised salt of diclofenac and pharmaceutically acceptable adjuvants.
10. A dry formulation according to any one of claims 1 to 5 for use in a therapeutic method of treating the human or animal body.
11. A dry formulation according to any one of claims 1 to 5 for use in the treatment of inflammatory conditions.
FO 7AIRS/cc/cs c Published 1985 at The Patent Office, State House, 55171 High Holborn, London WCIR 4TP. Further copies maybe obtained from The Patent Office, Sales Branch, St Mary Cray, Orpington, Kent BR5 3RD. Printed by Multiplex techniques ltd, St Mary Cray, Kent. Con- 1/87.
Q
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH350/87A CH673395A5 (en) | 1987-01-30 | 1987-01-30 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8801737D0 GB8801737D0 (en) | 1988-02-24 |
| GB2201089A true GB2201089A (en) | 1988-08-24 |
| GB2201089B GB2201089B (en) | 1990-05-16 |
Family
ID=4185019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8801737A Expired - Lifetime GB2201089B (en) | 1987-01-30 | 1988-01-27 | Parenteral suspensions of diclofenac. |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS63192716A (en) |
| KR (1) | KR880008808A (en) |
| AT (1) | AT397460B (en) |
| AU (1) | AU612343B2 (en) |
| BE (1) | BE1000442A4 (en) |
| CA (1) | CA1305058C (en) |
| CH (1) | CH673395A5 (en) |
| DE (1) | DE3802357A1 (en) |
| DK (1) | DK45588A (en) |
| ES (1) | ES2008420A6 (en) |
| FI (1) | FI880368A (en) |
| FR (1) | FR2611498B1 (en) |
| GB (1) | GB2201089B (en) |
| GR (1) | GR880100041A (en) |
| IE (1) | IE60453B1 (en) |
| IT (1) | IT1224241B (en) |
| LU (1) | LU87115A1 (en) |
| MY (1) | MY102662A (en) |
| NL (1) | NL8800231A (en) |
| NO (1) | NO880403L (en) |
| NZ (1) | NZ223343A (en) |
| PH (1) | PH23652A (en) |
| PT (1) | PT86644B (en) |
| SE (1) | SE8800228L (en) |
| YU (1) | YU15488A (en) |
| ZA (1) | ZA88638B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2675382A1 (en) * | 1991-04-19 | 1992-10-23 | Sandoz Sa | PARTICLES OF BIOLOGICALLY ACTIVE SUBSTANCES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| EP0574255A1 (en) * | 1992-06-11 | 1993-12-15 | INDENA S.p.A. | New derivatives of non-steroidal anti-inflammatory, analgesic and/or antipyretic substances, their use and pharmaceutical formulations containing them |
| WO2000067727A1 (en) * | 1999-05-11 | 2000-11-16 | Sanofi-Synthelabo | Galenic formulations of antithrombotic agents for subcutaneous administration |
| US6447806B1 (en) | 1999-02-25 | 2002-09-10 | Novartis Ag | Pharmaceutical compositions comprised of stabilized peptide particles |
| EP2402003A3 (en) * | 2005-06-17 | 2012-05-09 | Apr Applied Pharma Research S.A. | Diclofenac formulations and methods of use |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH675537A5 (en) * | 1988-03-25 | 1990-10-15 | Ciba Geigy Ag | |
| DE4140185C2 (en) * | 1991-12-05 | 1996-02-01 | Alfatec Pharma Gmbh | Medicament containing a 2-arylpropionic acid derivative in nanosol form and its preparation |
| DE4140183C2 (en) * | 1991-12-05 | 1995-12-21 | Alfatec Pharma Gmbh | Retard form for a medicine containing flurbiprofen |
| DE4140184C2 (en) * | 1991-12-05 | 1995-12-21 | Alfatec Pharma Gmbh | Acute form for a medicine containing flurbiprofen |
| ZA949182B (en) * | 1993-12-02 | 1995-07-26 | South African Druggists Ltd | Pharmaceutical composition |
| GB0207529D0 (en) * | 2002-04-02 | 2002-05-08 | Norbrook Lab Ltd | Injectable veterinary composition for small animals |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1373913A (en) * | 1970-12-17 | 1974-11-13 | Glaxo Lab Ltd | Pharmaceutical compositions |
| DE2914788A1 (en) * | 1979-04-11 | 1980-10-16 | Nattermann A & Cie | PARENTERAL APPLICABLE, STABLE DRUG SOLUTIONS WITH ANTI-INFLAMMATORY EFFECT |
| DE3324193A1 (en) * | 1983-07-05 | 1985-01-17 | Troponwerke Gmbh & Co Kg | DEPOT ANTIPHLOGISTICS |
| DE3328401A1 (en) * | 1983-08-05 | 1985-02-21 | Merckle GmbH, 7902 Blaubeuren | INJECTABLE SOLUTION FOR TREATING INFLAMMATION |
| EP0152379A3 (en) * | 1984-02-15 | 1986-10-29 | Ciba-Geigy Ag | Process for preparing pharmaceutical compositions containing unilamellar liposomes |
| DE3421468A1 (en) * | 1984-06-08 | 1985-12-19 | Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim | LIPID NANOPELLETS AS A CARRIER SYSTEM FOR MEDICINAL PRODUCTS FOR PERORAL USE |
| IE58110B1 (en) * | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
| US5002940A (en) * | 1984-11-06 | 1991-03-26 | Ciba-Geigy Corporation | Solid drug formulations and stable suspensions |
| DE3446873A1 (en) * | 1984-12-21 | 1986-07-10 | Merckle Gmbh | LIQUID DICLOFENAC PREPARATIONS |
| IT1207994B (en) * | 1986-01-03 | 1989-06-01 | Therapicon Srl | WATER SOLUBLE SALTS OF ANTI-INFLAMMATORY AND ANALGESIC ADAPTITY COMPOUNDS, THEIR PREPARATION AND USE IN PHARMACEUTICAL COMPOSITIONS. |
| DE3607339A1 (en) * | 1986-03-06 | 1987-09-10 | Merck Patent Gmbh | PHARMACEUTICAL PREPARATION |
-
1987
- 1987-01-30 CH CH350/87A patent/CH673395A5/de not_active IP Right Cessation
-
1988
- 1988-01-19 MY MYPI88000041A patent/MY102662A/en unknown
- 1988-01-25 SE SE8800228A patent/SE8800228L/en not_active Application Discontinuation
- 1988-01-27 GB GB8801737A patent/GB2201089B/en not_active Expired - Lifetime
- 1988-01-27 PH PH36414A patent/PH23652A/en unknown
- 1988-01-27 YU YU00154/88A patent/YU15488A/en unknown
- 1988-01-27 LU LU87115A patent/LU87115A1/en unknown
- 1988-01-27 FI FI880368A patent/FI880368A/en not_active IP Right Cessation
- 1988-01-27 DE DE3802357A patent/DE3802357A1/en not_active Ceased
- 1988-01-28 CA CA000557536A patent/CA1305058C/en not_active Expired - Lifetime
- 1988-01-28 PT PT86644A patent/PT86644B/en not_active IP Right Cessation
- 1988-01-28 NZ NZ223343A patent/NZ223343A/en unknown
- 1988-01-28 FR FR888800972A patent/FR2611498B1/en not_active Expired - Lifetime
- 1988-01-28 JP JP63016006A patent/JPS63192716A/en active Pending
- 1988-01-29 NL NL8800231A patent/NL8800231A/en not_active Application Discontinuation
- 1988-01-29 BE BE8800109A patent/BE1000442A4/en not_active IP Right Cessation
- 1988-01-29 ZA ZA88638A patent/ZA88638B/en unknown
- 1988-01-29 ES ES8800262A patent/ES2008420A6/en not_active Expired
- 1988-01-29 DK DK045588A patent/DK45588A/en not_active Application Discontinuation
- 1988-01-29 AU AU11102/88A patent/AU612343B2/en not_active Ceased
- 1988-01-29 KR KR1019880000740A patent/KR880008808A/en not_active Application Discontinuation
- 1988-01-29 NO NO880403A patent/NO880403L/en unknown
- 1988-01-29 IE IE25088A patent/IE60453B1/en not_active IP Right Cessation
- 1988-01-29 GR GR880100041A patent/GR880100041A/en unknown
- 1988-01-29 AT AT0018588A patent/AT397460B/en not_active IP Right Cessation
- 1988-08-21 IT IT47557/88A patent/IT1224241B/en active
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2675382A1 (en) * | 1991-04-19 | 1992-10-23 | Sandoz Sa | PARTICLES OF BIOLOGICALLY ACTIVE SUBSTANCES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| WO1992018105A1 (en) * | 1991-04-19 | 1992-10-29 | Sandoz Ltd. | Improvements in pharmaceutical compositions |
| GB2269536A (en) * | 1991-04-19 | 1994-02-16 | Sandoz Ltd | Improvements in pharmaceutical compositions |
| GB2269536B (en) * | 1991-04-19 | 1995-05-10 | Sandoz Ltd | Electrostatically protected peptide particles for pharmaceutical use |
| AT410896B (en) * | 1991-04-19 | 2003-08-25 | Novartis Pharma Gmbh | BIODICALLY ACTIVE PEPTIDE CONTAINING PARTICLES |
| EP0574255A1 (en) * | 1992-06-11 | 1993-12-15 | INDENA S.p.A. | New derivatives of non-steroidal anti-inflammatory, analgesic and/or antipyretic substances, their use and pharmaceutical formulations containing them |
| SG81182A1 (en) * | 1992-06-11 | 2001-06-19 | Indena Spa | New derivatives of non-steroidal anti- flammatory, analgesic and/or antipyretic substances, their use and pharmaceutical formulations containing them |
| US6447806B1 (en) | 1999-02-25 | 2002-09-10 | Novartis Ag | Pharmaceutical compositions comprised of stabilized peptide particles |
| WO2000067727A1 (en) * | 1999-05-11 | 2000-11-16 | Sanofi-Synthelabo | Galenic formulations of antithrombotic agents for subcutaneous administration |
| FR2793418A1 (en) * | 1999-05-11 | 2000-11-17 | Synthelabo | GALENIC FORMULATIONS OF ANTITHROMBOTIC AGENTS FOR SUBCUTANEOUS ADMINISTRATION |
| EP2402003A3 (en) * | 2005-06-17 | 2012-05-09 | Apr Applied Pharma Research S.A. | Diclofenac formulations and methods of use |
| EP3103441A1 (en) * | 2005-06-17 | 2016-12-14 | Apr Applied Pharma Research S.A. | Diclofenac formulations and methods of use |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19960127 |