LU87115A1 - SUSPENSIONAL PARENTERAL - Google Patents

Description

- 87 / B 52 7U

r ~. 0 ^^ | J GRAND-Di CHH DE LUXEMBOURG

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n '":, &« = Monsieur le Ministre

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., (i,. 27 i to four 1988 de l'Economie et des Classes Moyennes uv *> s *.

LESiEä Service de la Propriété Intellectuelle Titre ûelivre LUXEMBOURG

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Demande de Brevet d'invention, <* I. Requête

La société dite; ........ CIBA-GEIGY AG, Klybeckstrasse ..... 141, ......... (2? CH-4002 BASEL (Suisse), représentée par Monsieur Jacques de Muyser, agissant en .qualité de mandataire -......................................... ....-............................................. .................................................. ...................... .......................... (3rd > déposeint) ce .................. vingt-sept janvier 1900 quatre-vingt huit __________ (4) à ....... 1.5 ...... .............. heures, au Ministère de l'Économie et des Classes Moyennes, à Luxembourg: 1. la présente requête pour l'obtention d'un brevet d'invention concernant: .. .... "Parenterals; ...... suspensions." .................................. .................................................. ................................... ............. (5 ) "......, ......., ........... ...................... ; ...................................... everywhere .......... ......................................, ........... ......... ..... ................; ................, Γ ............... ..........

2. la descnption en langue ............................................ ............................................. de 1 invention en trois exemplaires; 3.. / ................................................. ... planches de dessin, en trois exemplaires; 4. la quittance des taxes versées au Bureau de l’Enregistrement à Luxembourg, le ^ Z3 anv ^ ®r ..... ^ 988.

5. la délégation de pouvoir, datée de .............? A§el ..................... ... .. each 10 décembre 1987; 6. le document d’ayant cause (authorization); déclare (nt) en assumant la responsabilité de cette déclaration, que l '(es) inventeurs) est (sont): (6) - Leo ..... GELLER, Rudolf ...... Wackernagel-Strasse ... ... 1 A., ....... CH-4125RIEHEN _____ (Suisse) - Peter GLANZMANN, ...... J, J, ........ Balmerstrasse 7, ..... ..CH-40.53 ...... BASEL______________________ (Suisse) ___________ _ _________________ _ ............................... .................................................. ...........

revendique (nt) pour la susdite demande de brevet la priorité d'une (des) demande (s) de (7) _______________brevet ....................... .. — ............. ................................ déposée ( s) en (8) ............ Suisse ............................... ..................................

le (9) 30 janvier 1987 ______________________________________________________ _ * ____________________ sous le N ° (10) 350 / 87-4 ........................... .................................................. ............................. ..................... .....................

au nom de (11) ................. la ..... déposante .................... ...............__....... ....... .................... .................................................. ....................

élit (élisent) domicile pour lui (elle) et, si désigné, pour son mandataire, à Luxembourg ............................. ........

35 boulevard Royal _ ____________ _____ _ ^ r) sollicite (nt) la délivrance d'un brevet d'invention pour l'objet décrit et représenté dans les annexes susmentionnées, avec ajournement de cette délivrance à ___________________ ^ 3 ...... .................................................. ............................................ mois. (13) ^ JL ^ éépesant / mandataire: ........................................ ......... ......... ..................... (14) for \ J ^, _ l). f / A Π · Procès-verbal de Dépôt

La susc ite demande de brevet a invention a été déposée au Ministère de l’Économie et des Classes Moyennes. Service-Jde la Propriété Intellectuelle à Luxembourg, en date du: 27 j anvier 1988 / v ytj », * V \ Pr- Ministre de l'Eco: jomie et des Classes Moyennes, vc à 15 ....... ............. heures f ί tföpL # · Λ Vp. d.

t ΐ: | Le chef du servi ^ dM | lapropriété intellectuelle, a ". assoit_Vj '_ / - 1 / V_ r \ h explications relatives au FdfcMOvyRf de dépôt. '’Y / / i * 4? 4. f \ (l) Siiv a lieu "Demande de certificat ô * adîhM ^ ai ^^ npmi« ^ al. A) a demande de brevei pnnnpal V-.. //..Du ....... * -Cimscnreie ^ nom, preoom profession adresse du demandeur, lorsque celui-ci est un païTmi iHnr n «'Wf <jénomiaaüon soaale forme juridique.address du sfete social, lorsque le demandeur esi une personne morale -' 3) mscnrt 87 / B 52 716

DEMANDING PRIORITY

the patent / Gbm. - Registration in: SWITZERLAND from: JANUARY 30, 1987 _ (No. 350 / 87-4) _

PATENT APPLICATION

in

Luxembourg

Applicant: CIBA-GEIGY AG

4002 BASEL (Switzerland)

Concerning · "Parenteral suspensions" - 1 -

Parenteral suspensions

The invention relates to a dry preparation, in particular a dry preparation obtainable by lyophilization, which can be used for the production of an aqueous, stable suspension for the parenteral application of a diclofenac salt, the use of this dry preparation for producing a stable, aqueous suspension containing the diclofenac salt and the application of this suspension in a process for the therapeutic treatment of the human body.

For the treatment of inflammatory diseases, e.g. Rheumatism, different drugs with different structures are available. Since inflammation is often chronic, treatment with anti-inflammatory drugs (anti-inflammatory drugs) usually has to be carried out over a longer period without interruption. In particular, some nonsteroidal anti-inflammatory drugs (NSAIDs) can cause inflammation in the entire gastrointestinal tract, especially ulcerative ventriculi, when administered orally.

The group of non-steroidal anti-inflammatory drugs of first choice includes the sodium salt of diclofenac, which is available under the trade name Voltaren® (Ciba-Geigy).

To increase drug safety, there is a need for new parenteral dosage forms for diclofenac or its salts, which are compared to the previously known parenteral injection solutions, e.g. according to German Offenlegungsschrift 2914788 and - 2 -

European patent application 185 374 »have the advantage of a very rapid onset of action with a long-lasting effect at the therapeutic level.

In the U.S. Patent 4,614,741 are described parenterally, in particular intramuscularly, suspensions to be administered with diclofenac or diclofenac sodium. Fatty oils such as sesame oil, olive oil etc. are used as suspension aids. In general, the use of fatty oils as auxiliary substances for parenteral application forms is disadvantageous, since they increase their viscosity, which can cause pain during application, see R. Voigt, Textbook of Pharmaceutical Technology, Verlag Chemie S. 383, 19.5.1.2.1. There is therefore also a need for suspensions to be administered intramuscularly, largely painlessly, containing a diclofenac salt, in particular diclofenac sodium.

The stated object is achieved by the present invention, which relates to a dry preparation containing a diclofenac salt in micronized form without disadvantageous auxiliary substances. After being suspended in aqueous carrier liquid, this dry preparation is converted into a dosage form to be administered parenterally.

The invention relates to a dry preparation, in particular a dry preparation obtainable by lyophilization, which can be used for the production of a stable, aqueous suspension for the parenteral application of a diclofenac salt. The dry preparation is characterized in that it contains a pharmaceutically acceptable and milcronized salt of diclofenac and optionally pharmaceutically acceptable additives.

A pharmaceutically acceptable salt of diclofenac, o- (2,6-dichloroanilino) phenylacetic acid, is especially an alkali metal salt, e.g. the sodium or potassium salt, or a salt with an amine, e.g. a mono-, di- or tri-Gi ~ Ci; alkylamine, e.g. Diethyl- or triethylamine, hydroxy-C2-Ci ^ -alkylamine, e.g. ethanol - 3-amine, hydroxy-Ca-Cij-alkyl-Ci-Cn-alkylamine, e.g. Dimethylethanolamine, or a quaternary ammonium salt, e.g. the tetramethylamraonium or choline salt of diclofenac.

The sodium and potassium salts of diclofenac are particularly preferred, see Merck Index, Tenth Edition No. 3066.

The Irocken preparation according to the invention contains the diclofenac salt, in particular the sodium or potassium salt of diclofenac, in micronized form.

The micronized diclofenac salt has a preferred average particle size less than 50, especially less than 20 microns. The usual size reduction techniques are used to produce particles with this particle size, e.g. Grinding in an air jet, ball or vibrator mill. Preference is given to methods known per se in an ultrasonic disintegrator, e.g. of the Branson Sonifier type, e.g. as in J. Pharm. 53 (9) 1040-45 (1965), or by means of high-speed stirring of a suspension, e.g. micronized with a Homorex stirrer from Brogli & Co, Basel. According to the preferred methods, micronization is carried out at about 500-10,000 revolutions per minute by the relevant salt of diclofenac in an organic solvent, e.g. Methanol, ethanol or propylene glycol, and dissolve in water or aqueous saline e.g. 2% saline, which may contain protective colloids such as gelatin or cellulose ether, e.g. Contains methyl cellulose or hydroxypropylmethyl cellulose, in low concentration (0.1-1%), microcrystalline precipitates at approx. 0 ° -5 ° and the stirred suspension obtained is filtered. The filter cake is carefully washed at low temperatures, e.g. approx. 0 ° -5 ° C, dried in a vacuum (e.g. less than 50 mbar, preferably at 0.5 mbar). The final drying can take place at approx. 50 ° -90 ° C.

- 4 -

Pharmaceutically acceptable additives that may be included in the dry preparation are e.g. Ionic isotonic additives such as table salt or nonionic isotonic additives, in particular framework formers such as sorbitol, mannitol or glucose. In particular, these additives, e.g. Table salt or mannitol, contained in the prescribed amounts in the dry preparation, which are necessary for the production of isotonic conditions of the suspension.

Other additives in low concentrations are e.g. emulsifiers useful as wetting agents, e.g. Phospholipids, e.g. Phosphatidylcholine (lecithin), Phosphatidylethanolamine (Kephalin), Phosphatidylserine, Phosphatidylinositol or mixtures of these lipids.

Preferred phospholipids are e.g. Soybean or egg lecithin or soybean or eikephaline of pharmaceutical purity or phospholipid mixtures with different phosphatidylcholine content, e.g. under the trade names Epikuron® 145, 170 or 200 (Lucas Meyer Hamburg) or Lipoid® (Lipoid KG Mannheim) 45, 80 or 100 commercially available lecithin mixtures.

The stated phospholipids can be present in the dry preparation in a ratio by weight of active ingredient to phospholipid of 1: 0.01 to 1: 1, preferably of 1: 0.1 to 1: 1.

Suitable additives in the dry preparation are also wetting agents or surfactants in the proper sense, which can be used for liquid pharmaceutical formulations, in particular nonionic surfactants of the fatty acid-polyhydroxy alcohol ester type such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty alcohols such as polyoxyethylene sorbitan monolaurate, oleate, stearate, palmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene t! - 5 - glycol-2000-stearate, in particular ethylene oxide-propylene oxide block polymers of the type Pluronic® (Wyandotte Chem. Corp.) or Synperonic® (ICI).

The surfactants mentioned can be present in the dry preparation in proportions by weight of active ingredient to surfactant from 0-4 bLs1: 0.1, preferably from 1: 0.03 to 1: 0.1.

The dry preparation according to the invention is produced by e.g. suspend the amount of the diclofenac salt intended for parenteral administration in micronized form in a suspension medium which optionally contains the pharmaceutically acceptable additives (auxiliaries), and that. Solvent removed.

Does the dry preparation contain water-soluble additives or auxiliary substances such as table salt, mannitol or glucose, which e.g. an aqueous suspension medium is preferred to produce isotonic conditions. After the additives have been dissolved in water for injection, the aqueous solution is preferably filtered and sterilized or sterile filtered. The micronized diclofenac salt is then added to this pretreated solution. The dry preparation can be prepared using known freeze-drying methods, e.g. by usually placing a certain amount of the suspension produced in suitable containers such as ampoules, e.g. Glass ampoules (vials), filled and the filled ampoules then frozen at approx. -40 ° to -50 ° C, especially at -45 ° C, and then at a pressure of approx. 0.05-0.6 mbar by slow heating lyophilized up to a final temperature of approx. 25 ° -55 ° C.

Does the dry preparation contain poorly soluble additives or auxiliary substances such as phospholipids, e.g. Lecithin, these additives are e.g. dissolved in a purified organic solvent such as tert-butanol, methanol, ethanol or methylene chloride and the micronized diclofenac salt suspended in this solution. After the organic solvent has been stripped off, the dry preparation coated with the additives, such as phospholipids, can be powdered into suitable containers, e.g. Prick ampoules, fill.

Surprisingly, the above-mentioned processes make it possible to produce dry preparations, in particular lyophilisates, and from them reconstitutable suspensions which are stable and suitable for injection.

The use of the dry preparation obtainable according to the above-mentioned methods for the production of injection suspensions is also the subject of the present invention. These injection suspensions can be administered parenterally, in particular intramuscularly, as injection formulations.

The dry preparation obtainable according to the invention is reconstituted before application as a suspension in the intended amount of liquid, in particular germ-free (pyrogen-free) water for injection.

Shaking again forms a suspension with a homogeneous distribution of the previously micronized active ingredient. Instead of a dry preparation containing the diclofenac salt and water-soluble additives such as table salt or mannitol, a dry preparation containing only the diclofenac salt (without additives) can also be suspended in the intended amount of liquid containing the water-soluble additives mentioned.

The particle size of the micronized active ingredient remains unchanged during the preparation of the suspension. So no significant crystal growth, e.g. observed through hydrate formation in the suspension to be applied. The active ingredient suspension also has the advantage that it does not adhere to the container wall of ampoules and can be easily and completely removed from the storage vessel with the syringe. In a particularly preferred embodiment, injection suspensions containing the usual doses of 50, 75 or 100 mg of diclofenac sodium are used, with a total volume of 1.0-3.0 ml, in particular 1.0-2.0 ml, mainly made 1.0 ml.

These suspensions can be used as "ready to use" preparations.

The present invention relates in particular to dry preparations and their use for the production of an aqueous suspension for the intramuscular application of diclofenac sodium. The dry preparation and the suspension preferably contain micronized diclofenac sodium with an average particle size of less than 20 micrometers and optionally auxiliaries such as table salt, mannitol, glucose and lipids such as lecithin or wetting agents of the SYNPER0NIC or PLURQNIC type.

The suspensions according to the invention can be used for parenteral (intramuscular) formulations for the treatment of pain conditions, inflammation and / or rheumatic diseases in warm-blooded animals (humans and animals). Daily dose amounts of approximately 25 to 200 mg of active ingredient can be applied, the individual dosage form containing the usual amounts of active ingredient, for example 25, 50, 75, 100 or 150 mg.

The following examples illustrate the invention without restricting it. Temperatures are given in degrees Celsius.

Example 1; a) Preparation of the lyophilizate

Composition per ampoule:

Diclofenac sodium 75 mg

NaCl 18 mg

Preparation of 10 ampoules: - 8-180 mg sodium chloride (ultrapure) are dissolved in 10 ml distilled water, and the solution is filtered through a membrane filter (0.2 micron pore size) and sterilized, e.g. in an autoclave at approx. 120 °. The sterile saline solution is cooled to 5 °. To the cooled solution, 750 mg of micronized diclofenac sodium salt (ultra pure) with an average particle size of less than 20 microns are added, suspended and deagglomerated, e.g. in a piston homogenizer or ultrasonic disintegrator. The crystal suspension is filled at 10 ° in 10 sterile glass ampoules with a filling volume of 1.0 ml. The ampoules are frozen at -45 °, lyophilized in a freeze-drying apparatus and then sealed.

b) Preparation of the active ingredient suspension for parenteral administration (reconstitution) _

The content of a glass ampoule containing 75 mg of diclofenac sodium as lyophilisate, preparation see example la), is mixed with 2.0 ml of sterile water for injection at room temperature and the lyophilisate is suspended by shaking. The suspension is taken up with a sterile syringe and can be applied intramuscularly.

Example 2i a) Analogously to Example la), lyophilisates containing 75 mg of diclofenac sodium or 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 can be prepared. These lyophilisates can also optionally contain an additional 0.01-10 mg Synperonic®.

b) Analogously to Example lb), one can lyophilisates containing 75 mg diclofenac sodium in 2.0 ml sterile water for injection containing 0.9% NaCl or lyophilisates containing 75 mg diclo- * »· - 9-fenac sodium and 100 mg mannitol or suspend 75 mg diclofenac sodium, 50 mg mannitol and 9 mg NaCl in 2.0 ml sterile water for injection at room temperature. These lyophilisates can optionally also be suspended with the addition of 0.01-10 mg Synperonic®. The isotonic suspensions produced can be taken up with a syringe and applied intramuscularly.

Example 3: a) Preparation of the dry preparation (powder)

Composition per ampoule:

Diclofenac sodium 75 mg

Lecithin (Epilcuron® 145, 170 or 200) 2-20 mg

Production of 10 ampoules:

The lecithin is dissolved in 10 ml of methylene chloride and the solution is filtered through a membrane filter (0.2 micron pore size). 750 mg of micronized diclofenac sodium salt with an average particle size of less than 20 micrometers are added to the filtered solution, suspended and deagglomerated (see Example 1a)). The solvent is then removed in vacuo. The lecithin-coated diclofenac sodium powder is filled into ampoules so that 75 mg diclofenac sodium are contained per ampoule.

b) Preparation of the active ingredient suspension for parenteral

Application_

Analogously to example lb), the content of a glass ampoule containing 75 mg of diclofenac sodium as a powder is coated with lecithin in 2.0 ml of sterile water for injection containing 0.9% NaCl or in 2.0 ml of sterile water containing an isotonic composition of NaCl and Mannitol suspended at room temperature.

'v - 9a - * · * * • Example 4: a) Preparation of the lyophilisate

Composition per ampoule:. .

Diclofenac sodium 75.00 mg

NaCl 5.40 mg

Mannitol 20.00 ng

Pluronic 0.07 ng

Preparation of 10 ampoules: 54.0 mg sodium chloride (ultrapure), 200.0 ng mannitol and 0.70 ng Pluronic are dissolved in 7.0 ml distilled water and the solution is filtered and sterilized through a membrane filter (0.2 micron pore size) , e.g. in an autoclave at approx. 120 ° C. The sterile suspension medium is cooled to 5 ° C. 750 ng k of micronized diclofenac sodium salt (ultrapure) with an average particle size of less than 20 microns are added to the cooled solution, suspended and disagglomerated, e.g. in a piston homogenizer or ultrasonic disintegrator. The crystal suspension is filled at 10 ° in 10 sterile glass ampoules with a filling volume of 0.800 g. The stinging coils are frozen at -45 °. lyophilized in a freeze-drying apparatus and then sealed.

b) Preparation of the active ingredient suspension for parenteral administration (reconstitution) _

The contents of the glass ampoule containing 75 mg of diclofenac sodium · · as lyophilisate (preparation see Example 4a) are mixed with 1.0 ml of sterile water for injection at room temperature and the lyophilisate is suspended by shaking. The suspension is aspirated with a sterile syringe and can be applied intramuscularly.

Claims (11)

1. Dry preparation for the preparation of a stable, aqueous suspension of diclofenac in salt form, characterized in that the dry preparation contains a pharmaceutically acceptable and micronizing, if appropriate, t salt of diclofenac and pharmaceutically acceptable additives. -2. Dry preparation obtainable by lyophilization according to claim 1. 3. Dry preparation according to claim 1 or 2 characterized by the content of diclofenac salt with an average particle size less than 50 microns. 4. Dry preparation according to claim 3 characterized by the content of diclofenac salt with an average particle size less than 20 microns. 5. Dry preparation according to claim 3, characterized by the content of diclofenac sodium with an average particle size of less than 20 micrometers. 6. A process for the preparation of a dry preparation according to any one of claims 1-4, characterized in that a diclofenac salt in micronized form is suspended in a suspension medium, which optionally contains the pharmaceutically acceptable additives, and the suspension medium is removed. 7. The method according to claim 6, characterized in that the diclofenac salt is suspended in micronized form in an aqueous suspension medium containing isotonic additives and the water is removed. - 11 - ft 8. The method according to claim 6, characterized in that the diclofenac salt is suspended in micronized form in an organic suspension medium containing phospholipids and the solvent is removed. 9. Use of a Irocken preparation according to one of claims 1-5 for the preparation of an aqueous suspension for parenteral administration containing a pharmaceutically acceptable and micronized salt of diclofenac and pharmaceutically acceptable additives. 10. Dry preparation according to one of claims 1-5 for use in a therapeutic method of the human or animal body. 11. Dry preparation according to one of claims 1-5 for use in the treatment of inflammatory conditions. FO 7.4 / RS / kg *