NO880403L - PARENTAL SUSPENSIONS. - Google Patents

Description

The present invention relates to a dry preparation, in particular a dry preparation that can be obtained by lyophilization which can be used for the preparation of an aqueous, stable suspension for parenteral administration of a diclofenac salt, the use of this dry preparation for the preparation of a stable, aqueous suspension containing the diclofenac salt and the use of this suspension in a method of therapeutic treatment of the human body.

For the treatment of inflammatory diseases, e.g. rheumatism, different drugs with different structures are available. As inflammation often occurs chronically, the treatment with anti-inflammatory drugs (anti-inflammatory drugs) must usually take place over a longer period of time without interruption. When administered orally, many non-steroidal anti-inflammatory drugs (NSAIDs) can cause inflammation in the entire gastrointestinal tract, especially ulcer ventriculi.

To the group of preferred non-steroidal anti-inflammatory agents is the sodium salt of diclofenac available under the trade name "Voltaren" (Ciba-Geigy).

In order to increase drug safety, there is a need for new parenteral administration forms for diclofenac, respectively its salts, which are compared to the hitherto known parenteral injection solutions, e.g. according to German Patent Application No. 2914788 and European Patent Application No. 185,374, it has the advantage of a very rapid onset of action with a long-lasting effect at a therapeutic level.

In the U.S. patent document no. 4,614,741 describes suspensions for parenteral, especially intramuscular administration with diclofenac or diclofenac sodium. As suspension aids, fatty oils such as sesame oil, olive oil, etc. are used. In general, the use of fatty oils as auxiliaries for parenteral administration forms is disadvantageous in that they increase their viscosity, which can cause pain during administration, see R. Voigt, "Lehrbuch der Pharmazeu- tischen Tecknologie", 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 essentially painless intramuscular administration.

This task is solved by the present invention if the object is a dry preparation containing a diclofenac salt, in finely divided form without harmful excipients. This dry preparation is transferred by suspension in an aqueous carrier bag to an administration form for parenteral administration.

The invention relates to a dry preparation, in particular a dry preparation which can be obtained by lyophilization, which can be used for the production of a stable, aqueous suspension for parenteral administration of diclofenac salt. The dry preparation is characterized by the fact that it contains a pharmaceutically acceptable and finely divided salt of diclofenac and possibly pharmaceutically acceptable added substances.

A pharmaceutically acceptable salt of diclofenac, o-(2,6-dichloroaneline)-phenylacetic acid, is particularly an alkali metal salt, e.g. the sodium or potassium salt, or a salt with an amine, e.g. a mono-, di- or tri-C 1 -C 4 alkylamine, e.g. diethyl- or triethylamine, hydroxy-C₁-C₁₆ alkylamine, e.g. ethanolamine, hydroxy-C2-C4-alkyl-C1-C4-alkylamine, e.g. dimethylethanolamine, or a quaternary ammonium salt, for example the tetramethylammonium or choline salt of diclofenac.

Particularly preferred is the sodium and potassium salt of diclofenac, see Note Index, tenth edition no. 3066.

The dry preparation according to the invention contains the diclofenac salt, especially the sodium or potassium salt of diclofenac in finely divided form.

The finely divided diclofenac salt has a preferred average particle size of less than 50, especially less than 20 µm. For the production of particles with this particle size, common comminution techniques are used, e.g. the mill in an air jet, ball, or vibrator mill. Preferably, it is crushed by a method known per se by an ultrasonic disintegrator, e.g. of the "Branson sonifier" type, e.g. as described in J. Pharm. Pollock. 53 (9) 1040-45 (1965), or by means of high-frequency stirring of a suspension, e.g. with a stirrer of the "homorex" type from the company Brogli & Co., Basel. According to the preferred method, one finely divides at approx. 500-10<*>000 revolutions per minute, by dissolving the relevant salt of diclofenac in an organic solvent, e.g. methanol, ethanol, or propylene glycol, and precipitates in water or aqueous salt solution, e.g. 2% saline solution which possibly contains protective colloids such as gelatin or cellulose ether, e.g. methylcellulose or hydroxypropylmethylcellulose, in low concentration (0.1 - 1%), in microcrystalline form at 0-5°C, and the obtained, stirred suspension is filtered. The filter cake is carefully dried at a low temperature, e.g. about. 0-5°C in vacuum (e.g. at less than 50 millibar, preferably at 0.5 millibar). Post-drying can take place at 50-90°C.

Pharmaceutically acceptable additives that can be found in the dry preparation are e.g. ionic isotonic things such as table salt or non-ionic isotonic additives, especially lattice formers such as sorbitol, mannitol, or glucose. In particular, these additives are found, e.g. common salt or mannitol, in prescribed amounts in the dry preparation required for preparation under isotonic conditions of the suspension. Additional additives in low concentrations are e.g. emulsifiers that can be used as wetting agents, e.g. phospholipids, e.g. phosphatidylcholine, (lecithin), phosphatidylethanolamine (kephalin), phosphatidylserine, phosphatidylinositol or mixtures of these lipids.

Preferred phospholipids are e.g. soya or egg lecithin or soya or egg kephalin of pharmaceutical purity, or for pharmaceutical use allow phospholipid mixtures with different phosphatidylcholine content, e.g. lecithin mixtures available under the trade names "Epikuron 145", "170" or "200" (Lucas Meyer Hamburg) or "Lipoid (Lipoid KG Mannheim) 45", "80" or "100".

The mentioned phospholipids can be present at a weight ratio between active substance and phospholipid of 1:0.01 to 1:1, preferably from 1:0.1 to 1:1, in the dry preparation.

Combined additives in dry preparations are also humectants for liquid pharmaceutical preparations or surfactants in the true sense, especially non-ionic surfactants of the fatty acid polyhydric alcohol ester type such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of the fatty acid polyhydroxy alcohol ester as polyoxyethylene sorbitan monolaurate, -oleate,

-stearate, -palmitate, -tristearate or -trioleate, the polyethylene glycol fatty acid ester such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, especially ethylene oxide-propylene oxide block polymers of the "pluronic" type

(Wyandotte Chem. Corp.) or "synperonic" (ICI).

The mentioned surfactants can be present in a weight ratio between active substance and surfactant of 1:1.0 x 10"<4> to 1:0.1, preferably from 1:0.03 to 1:0.1, in the dry preparation.

The dry preparation according to the invention is prepared by suspending e.g. the amount of the diclofenac salt planned for parenteral administration in finely divided form in a suspension medium which possibly contains pharmaceutically acceptable additives (excipients) and removes the solvent.

If the dry preparation contains water-soluble additives or excipients such as coking clay, mannitol or glucose, which e.g. is required to produce isotonic conditions, an aqueous suspension medium is preferred. After dissolving the additives in water for injection, the aqueous solution is preferably filtered and sterilized or sterile filtered. The finely divided diclofenac salt is then added to the solution which has been pre-treated in this way. The preparation of the dry preparation can take place by known freeze-drying methods, e.g. by filling a specific amount of the prepared suspension, usually in suitable containers, such as ampoules, e.g. glass ampoules (bottles) and the filled ampoules are then frozen at -40° to -50°C, especially at -45°C, and then lyophilized at a pressure of approx. 0.05 - 0.6 millibar when slowly heated to a final temperature of approx. 25° - 55°C.

Does the dry preparation contain additives that are poorly soluble in water or excipients such as phospholipids, e.g. lecithin, these conditions dissolve in e.g. in a purified organic solvent such as tert-butanol, methanol, ethanol or methylene chloride and in this solution the finely divided diclofenac salt is suspended. After removing the organic solvent, it can be filled with additives, such as phospholipids, and the dry preparation can be coated as a powder in suitable containers, e.g. ampoules.

Surprisingly, the aforementioned method succeeds in producing dry preparations, especially lyophilisates, and hence reconstructable suspensions that are stable and suitable for injection.

Use of the dry preparation obtained by the aforementioned method for the production of injection suspensions is also an object of the present invention. These injection suspensions can be administered as injection preparations parenterally, especially intramuscularly.

The dry preparation obtained according to the invention is reconstituted before administration as a suspension in the predetermined amount of liquid, especially germ-free (pyrogen-free) water for injection.

Upon shaking, a suspension with homogeneous distribution of the previously finely divided active substance forms again. Instead of a dry preparation containing the diclofenac salt and water-soluble additives, such as common salt or mannitol, a dry preparation containing only the diclofenac salt (without additives) can also be suspended in the predetermined amount of liquid containing the aforementioned water-soluble additives.

The particle size of the finely divided active substances remains unchanged during the preparation of the suspension. Consequently, no significant crystal weight is observed, e.g. by hydrate formation, in the suspension to be administered. The suspension of active substance also has the advantage that it does not adhere to the container wall of the ampoules and can be easily and completely removed with the syringe from the supply container. In a particularly preferred embodiment, injection suspensions containing the usual doses of 50, 75 or 100 mg of diclofenac sodium are prepared, with a total volume of 1.0 - 3.0 ml, i.e. especially 1.0 - 2.0 ml, above all 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 preparation of an aqueous suspension for intramuscular administration of diclofenac sodium. The dry preparation and the suspension preferably contain finely divided diclofinac sodium with an average particle size of less than 20 ytm and possibly excipients such as sodium bicarbonate, mannitol, glucose as well as lipids such as lecithin or functional agents of the "synperonic" or "pluronic" type.

The suspensions according to the invention can be used for parenteral (intramuscular) preparations for the treatment of pain conditions, inflammation and/or rheumatic diseases in water-blooded animals (humans and animals). Daily dose amounts from approx. 25 to 200 mg of active substance, where the individual forms of administration contain the usual amount of active substance of e.g. 25, 50, 75, 100 or 150 milligrams.

The following, non-limiting, examples illustrate the invention.

Example 1:

a) Preparation of the lyofill.

Preparation of 10 ampoules:

180 mg sodium chloride (pure) is dissolved in 10 milliliters of distilled water and the solution is filtered through a membrane filter (pore size 0.2 µm) and sterilized,

e.g. in an autoclave at approx. 120°C. The sterile saline solution is cooled to 5°C. To the cooled solution is added 750 milligrams of finely divided diclofenac sodium salt (pure) with an average particle size of less than 20 µm, it is suspended and deagglomerated residue, e.g. in a flask homogenizer or an ultrasonic disintegrator. The crystal suspension is filled at 5°C into 10 sterile

glass ampoules at full volume 1.0 milliliters. The ampoules are frozen at -45°C, lyophilized in a freeze-drying apparatus and then closed. b) Preparation of the suspension of active substance for parenteral administration (reconstltus. lon).

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

Example 2:

a) Analogous to example la), lyoflisates containing 75 mg diclofenac sodium and 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 can, if desired, also contain 0.01 - 10 mg "synperonic". b) Analogous to example lb), lyophilisates containing 75 mg of diclofenac sodium can be suspended in 2.0 ml of sterile

water for injection containing 0.9% NaCl or lyophilisate 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 at room temperature

perature. If desired, these lyophilizers can also be suspended with the addition of 0.01 - 10 mg "synperonic". The prepared isotonic suspensions can be taken up with a syringe and administered intramuscularly.

Example 3:

a) Preparation of the dry preparation (powder)

Composition per ampoule:

Preparation of 10 ampoules:

The lecithin is dissolved in 10 ml of methylene chloride and the solution is filtered through a membrane filter (pore size 0.2 µm). 750 mg of finely divided diclofenac sodium salt with an average particle size of less than 20 µm is added to the filtered solution, it is suspended and deagglomerated (see Example 1a). The solvent is then removed under vacuum. The lecithin-coated diclofenac sodium powder is filled into ampoules so that each ampoule contains 75 mg of diclofenac sodium.

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

Analogous example lb) suspend the contents of a glass ampoule containing 75 mg of diclofenac sodium as powder 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 at room temperature.

Example 4:

a) Preparation of the lvofilizate.

Composition per ampoule:

Preparation of 10 ampoules:

54.0 mg of sodium chloride (highest purity), 200.0 mg of mannitol and 0.70 mg of "pluronic" are dissolved in 7.0 ml of distilled water and the solution is filtered through a membrane filter (pore size 0.2 pm) and sterilized, e.g. . in an autoclave at approx. 120°C. The sterile suspension is cooled to 5°C. 750 mg of finely divided diclofenac sodium salt (highest purity) with an average particle size of less than 20 µm is added to the cooled solution, it is suspended and deagglomerated, e.g. in a flask homogenizer or ultrasonic disintegrator. The crystal suspension is filled at 5°C into 10 sterile glass ampoules with a full volume of 0.800 g. The ampoules are frozen at -45°C, lyophilized in a freeze-drying apparatus and then closed.

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

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

Claims (8)

1. Method for producing a dry preparation of diclofenac in salt form, characterized by suspending a pharmaceutically acceptable and finely divided salt of diclofenac in a suspension medium, possibly introducing pharmaceutically acceptable additives and removing the suspension medium. 2. Method according to claim 1, characterized in that the dry preparation is prepared by lyophilization. 3. Method according to claim 1, characterized in that the dry preparation is prepared from a diclofenac salt with an average particle size of less than 50 pm. 4. Method according to claim 3, characterized in that the dry preparation is prepared from a diclofenac salt with an average particle size of less than 20 pm. 5. Method according to claim 4, characterized in that the dry preparation of diclofenac sodium is produced with an average particle size of less than 20 pm. 6. Process for producing a dry preparation according to one of claims 1-4, characterized in that diclofenac sodium is suspended in finely divided form in an aqueous suspension medium, which possibly contains the pharmaceutically acceptable additives, and the suspension medium is removed. 7. Method according to claim 6, characterized in that diclofenac sodium is suspended in finely divided form in an aqueous suspension medium containing isotonic additives and the water is removed. 8. Method according to claim 6, characterized in that diclofenac sodium is suspended in finely divided form in an organic suspension medium containing phospholipids and the solvent is removed.