NL8800231A - PARENTERAL SUSPENSIONS. - Google Patents

Description

N.0. 34918

Parenteral suspensions.

The invention relates to a dry preparation, in particular to a dry preparation obtainable by freeze-drying, which can be used for preparing a stable suspension in water for the parenteral administration of a diclofenac salt, on the application of this dry preparation for the preparation of a stable suspension in water containing the diclofenac salt and for the use of this suspension in a method for the therapeutic treatment of the human body.

For the treatment of inflammatory diseases, for example rheumatism, various drugs with different structures are available. Since inflammation often has a chronic course, treatment with anti-inflammatory drugs (anti-flammers) should usually be long-term and without interruption. In particular, many non-steroidal anti-inflammatory drugs (NSAID) when administered orally can cause inflammation in the entire gastrointestinal tract, especially in the ulcer ventriculi.

The group of the non-steroidal anti-inflammatory drugs of the first choice includes the sodium salt of diclofenac available under the tradename Voltarerf® (Ciba-Geigy).

In order to improve the reliability of drugs, there is a need for new parenteral dosage forms for diclofenac and its salts, which are superior to known parenteral injection solutions, e.g. according to German Offenlegungsschrift 2,914,788 and European patent application 185,374, have the advantage of a very fast-starting and long-lasting effect at a therapeutic level.

In U.S. Patent 4,614,741, suspensions to be administered parenterally, in particular intramuscularly, with diclofenac and. diclofenac sodium. Fat suspension oils such as sesame oil, olive oil and the like are used as suspension aids. Generally, the use of fatty oils as adjuvants for parenteral dosage forms is disadvantageous because they increase their viscosity, which may cause pain upon application; see R. Voigt, Lehrbuch der Pharmazeutischen Technologie, Verlag Chemie, p. 383, 35 19.5.1.2.1. There is therefore also a need for suspensions to be administered almost painlessly, which are to be administered intramuscularly, containing a diclofenac salt, in particular diclofenac sodium.

The problem identified is solved by the invention which c. 8 6 0 02 3 1 2 is directed to a dry formulation containing a micronized diclofenac salt without deleterious auxiliaries. This dry preparation is transferred after suspension in an aqueous carrier liquid in a dosage form to be used.

The invention relates to a dry preparation, in particular to a dry preparation obtainable by freeze-drying, which can be used for the preparation of a stable suspension in water for the parenteral administration of a diclofenac salt. The dry preparation is characterized in that it contains a pharmaceutically acceptable and micronized salt of diclofenac and optionally pharmaceutically acceptable additives.

A pharmaceutically acceptable salt of diclofenac, o- (2,6-dichloroanilino) phenylacetic acid, is in particular an alkali metal salt, e.g. the sodium or potassium salt, or an amine-derived salt, e.g. a mono-, di- or tri-C 1 -C 3 / alkylamine, such as diethyl or triethylamine, hydroxy-C 2 -C 4 alkylamine, such as ethanol amine, hydroxy-C 2 -C 4 alkyl-C 1 -C 4 alkylamine such as dimethyl ethanol amine, or a quaternary ammonium salt, such as the tetramethylammonium or choline salt of diclofenac.

Particular preference is given to the sodium and potassium salt of diclofenac; see Merck Index, tenth edition No. 3066.

The dry 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 preferably has an average particle size of less than 50, especially less than 20 microns. Conventional comminution techniques are used for the preparation of particles of this particle size, for example grinding in an air jet, ball or vibratory mill. Preferably, micronization is carried out in accordance with a method known per se in an ultrasonic disintegrator, for example of the Branson Sonifier type, as described in J. Pharm. Sci. 53 (9) 1040-45 (1965), or by rapid stirring of a suspension, e.g. with a Homorex stirrer from Brogli & Co, Basel. According to the preferred methods, micronization is performed at about 500-10,000 revolutions per minute, the respective salt of diclofenac being dissolved in an organic solvent, for example methanol, ethanol or propylene glycol, and in water or in a salt solution in water, for example 2- percent kitchen salt solution, optionally protective colloids such as gelatin or cell-40 lulose ethers, eg methyl cellulose or hydroxypropyl methyl cellulose in .8800231 t 4 3 contains a small concentration (0.1-1¾), crystallizes out microcrystalline at 0-5 ° C and filters the resulting stirred suspension. The filter cake is carefully prepared at low temperatures, e.g. 0-5 ° C, dried under vacuum (e.g. less than 50 mbar, preferably at 0.5 mbar). Post-drying can take place at about 50-90 ° C.

Pharmaceutically acceptable additives that may be present in the dry formulation are, for example, ionic isotonic additives such as table salt or nonionic isotonic additives, especially skeletal formers such as sorbitol, mannitol and glucose. In particular, these additives, such as table salt or mannitol, are present in the dry formulation in the amounts prescribed for effecting isotonic conditions of the suspension.

Further additives in low concentrations are, for example, emulsifying agents useful as a wetting agent, such as phospholipids, for example phosphatidylcholine (lecithin), phosphatidylethanol amine (kephalin), phosphatidylserine, phosphatidylinositol and mixtures of these lipids.

Preferred phospholipids are, for example, soybean or egg lecithin or soybean or egg cephalin of pharmaceutical purity or phospholipid mixtures of different phosphatylcholine content permitted for pharmaceutical use, e.g. with the trade names Epikurorl® 145, 170 or 200 (Lucas Meyer Hamburg) or Lipoid (Lipoid KG Mannheim) 45, 80 or 100 commercially available Tecithin mixtures.

The said phospholipids can be present in the dry preparation in weight ratios between active substance and phospholipid from 1: 0.01 to 1: 1, preferably from 1: 0.1 to 1: 1.

Suitable additives for the dry preparation are furthermore useful wetting agents or tensides which are usable for liquid pharmaceutical preparations, in particular non-ionic surfactants of the type fatty acid polyhydroxy alcohol ester such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene additions of fatty acid polyhydroxy alcohol esters such as polyoxyethylene sorbitan monolaurate, oleate, stearate, palmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethylene stearate polyethylene-35 glycol-2000 stearate, in particular ethylene oxide-propylene oxide block polymers of the type PI uronitf® (Wyandotte Chem. Corp.) or Synperonic® (ICI).

The surfactants mentioned may be present in the dry preparation in weight ratios of active substance in the range from 1: 0.0001 to 1: 0.1, preferably from 1: 0.03 to 40 1: 0.1.

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The dry preparation according to the invention is prepared, for example, by suspending the amount of the diclo-phenac salt intended for parenteral administration in micronized form in a suspension medium, which optionally contains the pharmaceutically acceptable additives (excipients) and removing the solvent.

When the dry preparation contains water-soluble additives or auxiliary substances such as table salt, mannitol or glucose, which are necessary, for example, for the creation of isotonic conditions, an aqueous suspension medium is preferred. After dissolving the additives in water suitable for injection, the aqueous solution is preferably filtered and sterilized or sterile filtered. The micronized diclofenac salt is then added to this pre-treated solution. The preparation of the dry preparation can be carried out by known freeze-drying methods, for example, by placing a certain amount of the prepared suspension in suitable containers, such as ampoules, for example ampoules, in the usual manner, and then filling the filled ampoules at about -40 to - 50 ° C, especially at -45 ° C, and then freeze-dried at a pressure of about 0.05-0.6 mbar by slow heating to a final temperature of about 25-55 ° C.

When the dry preparation contains sparingly water-soluble additives or auxiliary substances such as phospholipids, for example lecithin, these additives are dissolved, for example, in a purified organic solvent such as tert-butanol, methanol, ethanol or dichloromethane and the micronized diclofenac salt is dissolved in this solution. suspended. After removal of the organic solvent, the dry preparation coated with the additives such as phospholipids can be powdered into suitable vessels, such as ampoules.

Surprisingly, dry preparations, in particular lyophilizates and reconstitutable suspensions therefrom, which are stable and suitable for injection, can be prepared by said process.

The use of the dry preparation obtained according to this method for the preparation of injection suspensions is also subject of the invention. These injection suspensions can be administered as injection preparations parenterally, in particular intramuscularly.

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

40 By shaking again a suspension with homogeneous distribution is formed. 8 8 0 C L; :

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5 of the pre-coated 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) in the intended amount of liquid containing said water-soluble additives are suspended.

The particle size of the micronized active substance remains unchanged in the preparation of the suspension. For example, no significant crystal growth, for example due to hydrate formation, is observed in the suspension to be administered. The suspension of the active substance also has the advantage that it does not adhere to the container wall of ampoules and can be easily and completely withdrawn from the storage container with a syringe. In a particularly preferred embodiment, injection suspensions containing the usual doses of 50, 75 or 100 mg diclofenac sodium, with a total volume of 1.0-3.0 ml, in particular 1.0-2.0 ml and specially prepared 1.0 ml.

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

The invention particularly relates to dry preparations and their use for the preparation of an aqueous suspension for the intramuscular administration 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 auxiliary agents such as table salt, mannitol, glucose and lipids such as lecithin or wetting agent of the SYNPERONIC or PLURONIC type.

The suspensions according to the invention can be used for parenteral (intramuscular) preparations for the treatment of pain states, inflammations and / or rheumatic diseases in warm blooded animals (humans and animals). Daily doses of about 25 to 200 mg of active ingredient can be administered, the separate presentation containing the usual amounts of active ingredient of, for example, 25, 50, 75, 100 or 150 mg.

The examples below illustrate the invention without limiting it. The temperatures stated are temperatures in degrees Celsius.

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Example I; a) Preparation of the Ivophilisate Composition per ampoule: diclofenac sodium 75 mg 5 NaCl 18 mg

Preparation of 10 ampoules: 180 mg of sodium chloride (very pure) is dissolved in 10 ml of distilled water and the solution is filtered through a membrane filter (0.2 µm pore size) and sterilized, for example in an autoclave at about 120 ° C. The sterile table salt solution is cooled to 5 °. To the cooled solution, 750 mg of micronized diclofenac sodium salt (very pure) with an average particle size of less than 20 µm are added, suspended and desagglomerated, for example in a piston homogenizer or ultrasonic disintegrator. The crystal suspension is placed in 5 sterile ampoules with 1.0 ml fill volume at 5 °. The ampoules are frozen at -45 °, lyophilized in a lyophilizer and then sealed.

B) Preparation of the suspension of the active substance for parenteral administration (reconstitution)

To the contents of a ampoule containing 75 mg of diclofenac sodium lyophilisate, prepared according to Example 1a), 2.0 ml of sterile water for injection is added at room temperature and the lyophilizate is suspended by shaking. The suspension is taken up with a sterile syringe and can be administered intramuscularly. Example II: a) Analogous to Example Ia), lyophilisates containing 75 mg diclofenac sodium or 75 mg diclofenac sodium and 100 mg mannitol or 75 mg diclofenac sodium, 50 mg mannitol and 9 mg NaCl can be prepared. These lyophilisates may optionally also contain 0.01-10 mg of Synperonic ™.

b) Analogous to Example Ib), lyophilisates containing 75 mg diclofenac sodium in 2.0 ml sterile water for injection containing 0.9 dat NaCl or lyophilization containing 75 mg diclofenac sodium and 100 mg mannitol or 75 mg diclofenac sodium , 50 mg mannitol and 9 mg NaCl in 2.0 ml sterile water for injection, suspend at room temperature. Optionally, these lyophilisates can also be suspended with the addition of 0.01-10 mg of Synperonid®. The prepared isotonic suspensions can be taken up with a 40 syringe and administered intramuscularly.

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

Composition per ampoule: diclofenac sodium 75 mg 5 lecithin (EpikurorPl45, 170 or 200) 2-20 mg

Preparation of 10 ampoules:

The lecithin is dissolved in 10 ml of dichloromethane and the solution is filtered through a membrane filter (0.2 micron pore size).

To the filtered solution is added 750 mg of micronized diclofenac sodium salt with an average particle size of less than 20 micrometers and this is suspended and desagglomerated (see Example 1a)). The solvent is then removed under reduced pressure. The ampoules filled with lecithin diclofenac sodium powder are filled in such a way that they each contain 75 mg diclofenac sodium.

b) Preparation of the suspension of the active substance for parenteral administration

Analogous to Example 1b), the contents of a ampoule containing 20 75 mg diclofenac sodium powder, are coated with lecithin in 2.0 ml 0.9% NaCl containing sterile water for injection or in 2.0 ml isotonic composition of Contains NaCl and mannitol containing sterile water suspended at room temperature.

Example IV: a) Preparation of the lvophilisate Composition per ampoule: diclofenac sodium 75.00 mg

NaCl 5.40 mg mannitol 20.00 mg 30 Pluronic 0.07 mg

Preparation of 10 ampoules: 54.0 mg of sodium chloride (very pure), 200.0 mg of mannitol and 0.70 mg of Pluronic are dissolved in 7.0 ml of distilled water and the solution is passed through a membrane filter (0.2 μm). pore size) filtered and sterilized, e.g. in an autoclave at approx.

120 ° C. The sterile suspension medium is cooled to 5 °. 750 mg of micronized diclofenac sodium salt (very pure) with an average particle size of less than 20 ml-40 crometer are added to the cooled solution and this is suspended and desagglomerated, for example in a piston homogenizer or an ultrasonic disintegrator. The crystal suspension is placed in 5 sterile glass ampoules with 0.800 g filling volume at 5 °. The ampoules are frozen at -45 °, lyophilized in a freeze-drying device and then sealed.

5 b) Preparation of the suspension of the active substance for parenteral administration (reconstitution)

To the contents of the glass ampoule containing 75 mg of diclofenac sodium as lyophilisate (preparation according to example IVa)), 1.0 ml of sterile water is injected at room temperature and the lyo-10 filisate is suspended by shaking. The suspension is taken up with a sterile syringe and can be administered intramuscularly.

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Claims (11)

1. Dry preparation for the preparation of a stable suspension in water of diclofenac in salt form, characterized in that the dry preparation contains a pharmaceutically acceptable and micronized salt of diclofenac and optionally pharmaceutically acceptable additives, Dry preparation according to claim I, characterized in that it is obtained by freeze drying. Dry preparation according to claim 1 or 2, characterized in that it contains a diclofenac salt with an average particle size of less than 10 micrometers. Dry preparation according to claim 3, characterized in that it contains a diclofenac salt with an average particle size of less than 20 micrometers. Dry preparation according to claim 3, characterized in that it contains diclofenac sodium with an average particle size of less than 20 micrometers. 6. 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. Process according to claim 6, characterized in that the diclofenac salt is suspended in micronized form in an aqueous suspension medium containing the isotonic additives and the water is removed. Process 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 dry preparation according to any one of claims 30 1-5 for the preparation of an aqueous suspension for parenteral administration, which suspension contains a pharmaceutically acceptable and micronised salt of diclofenac and pharmaceutically acceptable additives. 10. A dry preparation according to any one of claims 1 to 5 for use in the therapeutic treatment of a human or animal body. A dry preparation according to any one of claims 1 to 5 for use in the treatment of inflammatory conditions. +++++++, 880023!