JPS63192716A - Suspension for non-oral administration - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention provides a method for preparing dry formulations, in particular aqueous stable suspensions for parenteral administration of diclofenac salts, obtainable by lyophilization. A dry formulation, the use of said formulation for the preparation of a stable aqueous suspension containing said diclofenac salt, and the use of said suspension in a method of human treatment.

[Problems to be solved by the prior art and the invention 3 Various drugs having various structures are used to treat inflammatory diseases, such as +7.
- Useful for the treatment of gore.

Because the inflammatory process is often long-term, uninterrupted long-term anti-inflammatory drug treatment is usually required. In particular, when administered orally, many non-steroidal anti-inflammatory drugs (NAID8) cause diseases of the entire gastrointestinal tract, especially gastric ulcers.

The sodium salt of diclofenac, available under the registered trademark Voltar*n (Chiper Kaigy), belongs to the group of primarily important non-steroidal anti-inflammatory drugs.

In order to improve drug safety, for example, German Open Publication No. 2
914788 and European Patent Application No. 185374, diclofenac and New parenteral dosage forms are needed for the salts.

Suspensions of diclofenac or diclofenac sodium for parenteral, especially intramuscular, administration are described in US Pat. No. 461
No. 4741.

Fatty oils such as sesame oil, olive oil, etc. are used as suspending media for these suspensions. Quite generally,
The use of fatty oils as adjuvants for parenteral dosage forms is inappropriate. This is because they increase the viscosity of the dosage form and cause pain to the patient when administered.
Pharmat@utiaehenT@chnolog
1*, V@rlag Ch@m1@* p, 38
3 Meeting 19.5.1.2.1). Accordingly, there is a need for a suspension containing a diclofenac salt, particularly diclofenac sodium, for substantially painless intramuscular administration.

[Means for solving the problem, action and effects of the invention]

The above objects of the invention are achieved by the present invention, which comprises a dry formulation KM containing diclofenac salt in micronized form without harmful adjuvants. After suspension in an aqueous liquid vehicle, the dry formulation is converted to a dosage form for parenteral administration.

The invention thus relates to a dry formulation, in particular a dry formulation obtainable by lyophilization, which can be used for the preparation of aqueous suspensions of diclofenac salts that are stable for parenteral administration. The dry formulation comprises a pharmaceutically acceptable and micronized salt of diclofenac as well as any desired pharmaceutically acceptable adjuvants.

Diclofenac, o-(2,6-dichloroanilino)
Pharmaceutically acceptable salts of phenylacetic acid are particularly alkali metal salts, such as sodium or potassium salts, or amine salts, such as 1 to 1 in the alkyl moiety or residue.
Seven-, di- or trialkylamines containing 4 carbon atoms, such as diethylamine or triethylamine, hydroxylamines containing 2 to 4 carbon atoms in the alkyl moiety, such as ethanolamine, on each of the alkyl moieties. 2 to 4 each in a row El to 4
Hydroxyalkylalkylamines having 5 carbon sons, such as dimethylethanolamine or quaternary ammonium salts, such as the tetramethylammonium salt or choline salt of diclofenac.

Particularly preferred salts of diclofenac are the sodium and potassium salts (Merck Index, 10th edition,
43066).

The dry formulation of the present invention is a diclofenac salt, particularly the sodium or potassium salt of diclofenac in micronized form.

Ultra-finely ground diclofenac salt, in ultra-finely ground form, contains 50
20 am, preferably less than 20 am. Particles of this size are obtained by conventional grinding methods, for example in an air die-gamma mill, a male mill or a vibrator mill. Ultrafine pulverization is described in, for example, J.

Pharm, Sc1.53 (9) 1040-10
45 (1965)), or by a known method using an ultrasonic disc inching grater of the Planson sonifier type, such as that described by Brogli & Co. This is preferably carried out by stirring using a Basel filter. In these preferred methods, micronization comprises:
Approximately 500-10. Dissolve a suitable salt of diclofenac in an organic solvent such as methanol, ethanol or globylene glycol at OOO rpm and then
In water or an aqueous salt solution at a temperature of ~5°C, e.g. additionally contains a protective colloid gelatin or a cellulose ether, e.g. methylcellulose, in low concentrations (0.1-1%), e.g. This is carried out by precipitating the salt of the cyclo7enac in ultrafine form in a sodium chloride solution and passing the resulting stirred suspension by mouth.

The filter cake is dried at a low temperature, for example about 0° to 5° C., under vacuum (eg 50 mbar, preferably less than 0.5 mbar). Freeze-drying is approximately 500-90℃
It will be held in

The pharmaceutically acceptable auxiliary substances that the dry formulation may contain can include, for example, ionic isotonic components such as sodium chloride or non-ionic components, especially pirdanes, such as sorbitol, mannitol, 4 L<u glucose. Preferably, the dry formulation contains these adjuvants, such as sodium chloride or mannitol, in the stated amounts necessary to establish the isotonic state of the suspension.

Furthermore, adjuvants present in lower concentrations, such as emulsifiers used as wetting agents, such as phospholipids, such as phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine, phos-7-tidylcholintol or of these lipids. It is a mixture.

Preferred phospholipids are, for example, pharmaceutically pure soy or egg lecithin, or soy or egg heptaphalin, or mixtures of various phos-7-acylcholine phospholipids acceptable for pharmaceutical use, such as Ep1kuron®.
145, 170 or 200 (Lucas Mayer, Hanrug) or FiLipoid 45.80. or 1Oo
(Lipoid KG, Mannheim) is a mixture of lecithins commercially available as (Lipoid KG, Mannheim).

The above-mentioned phospholipid has a weight ratio of active ingredient to phospholipid of 1:0.01 to 1:1. Preferably l:0.1-1:
1 in solid formulations.

Furthermore, suitable adjuvants in dry formulations are wetting agents useful in liquid pharmaceutical formulations, or true surfactants, especially fatty acids? Nonionic surfactants of the hydroxyalcohol ester type, such as sorbitan monolaurate, monooleate,
Monostearates are also useful, such as hamotubamitate, sorbitan tristearate or trioleate, adducts of ethylene and fatty acid polyhydroxy alcohol esters, such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monostearate, trioleate, etc. Stearates or trioleates, I-lyethylene glycol fatty acid esters, such as polyoxyethyl stearate, I-diethylene glycol 400 stearate, polyethylene glycol 2000 stearate L
'-), Zollonik (trademark) type (Wyando) in 'I
tt.) or Syn (Ronik (Sho 11)) ethylene carbonate/7m propylene oxide polymer.

These surfactants have a weight ratio of active ingredient to active surfactant of 1:1. OX 10-' ~1: 0.1
, preferably present in the dry formulation in a ratio of 1:0.03 to 1:0.1.

The dry formulation of the invention comprises suspending an amount of diclofenac salt intended for parenteral administration in micronized form in a suspending medium containing the desired pharmaceutically acceptable adjuvants; It is then prepared by removing the solvent.

If the dry formulation contains water-soluble ingredients or adjuvants necessary for establishing isotonic conditions, such as sodium chloride, mannitol, or glucose, aqueous suspension media are preferred. After the adjuvant is dissolved in purified water for injection, the aqueous solution is preferably swished, sterilized, or sipped under sterile conditions. To this sterile solution, add micronized diclofenac salt. Preparation of dry formulations can be carried out using known freeze-drying methods, such as typically by filling a specified amount of the prepared suspension into a suitable container, such as an ampoule, e.g. 14
Freeze at 5°C, then about 0.05-0.6 mm Z-
Freeze-drying is carried out by warming to a final temperature of about 25-55° C. under pressure.

If the dry formulation contains adjuvants or ingredients that are not very soluble in water,
For example, when containing phospholipids, such as lecithin, the adjuvant is dissolved, for example, in a purified organic solvent, such as tert-butanol, i-nitol, ethanol or methylene chloride, and the micronized salt is then suspended in this solution. After removal of the organic solvent, the dry formulation coated with adjuvants such as phospholipids is filled into a suitable container (eg vial in powder form).

Surprisingly, the process of the invention allows dry formulations,
In particular, lyophilized formulations and suspensions that can be reconstituted and are stable and suitable for injection can be prepared from them.

The use of the dry formulation obtained by the process of the invention for the preparation of injection suspensions is also an object of the invention. These injection suspensions can be administered parenterally, preferably intramuscularly, as injection preparations.

The dry formulations of the invention are reconstituted as a suspension in a defined volume of liquid, particularly sterile (pyrogen-free) water for injection, prior to administration.

The previously micronized homogeneous suspension of the drug can be shaken again, preferably to form a polypropylene. Instead of a dry formulation containing diclofenac salt and a water-soluble adjuvant (e.g. chloride) or mannitol, a dry formulation containing only diclofenac salt (no adjuvant) containing the above water-soluble adjuvant , it is also possible to suspend it in a defined amount of liquid.

The particle size of the micronized drug remains unchanged during the preparation of the suspension. Therefore, no appreciable crystal growth, eg hydrate formation, is observed in the suspension to be administered. Suspensions of drugs also have the following advantages:

That is, the nuclear suspension does not stick to the walls of the ampoule and can be easily and completely removed from the ampoule with a syringe. A particularly preferred embodiment of the present invention has a total capacity of 1.0
~3. Od, preferably 1.0-2.0 ml, especially 1
．． For the preparation of an injectable suspension containing the usual dose of Diclofenac Sodium A30m1F, 751119 or 100q with a volume of 0Illllj.

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

The invention relates in particular to its use for the preparation of dry formulations as well as aqueous suspensions for intramuscular administration of diclofenac sodium. Dry formulations and suspensions preferably contain micronized diclofenac with an average particle size of less than 20 am and any desired adjuvants such as sodium chloride, mannitol,
Contains sorbitol as well as lipids such as lecithin or syn (wetting agents of the Ronik™ or Pluronic™ type).

The suspensions of the invention can be used for parenteral (intramuscular) administration for the treatment of pain conditions, inflammation, and/or somatic diseases in warm-blooded animals (humans and animals). Daily doses of 25 to 200 IIP of the active ingredient can be administered, while individual device forms can be administered at conventional doses of the drug, such as 25, 50, 75.
100 or 150~.

The following examples illustrate the invention, but are not intended to limit it in any way.

〔Example〕

Example 1 a) Preparation of lyophilized pharmaceutical formulation Composition of each angle Nidiclofenac sodium 75m9 Sodium chloride 18j Preparation of 910 angles: 180"19 sodium chloride (purified),
of distilled water and then pass the solution through a membrane filter (pore size:
0.2 tttn) and sterilize, for example, in an autoclave at about 120°C. Cool the sterile sodium chloride solution to 5°C. Micronized diclofenac sodium (purified) with an average particle size of less than 20 #71 is added to the cooled solution, and the resulting suspension is then deagglomerated, for example in a piston homogenizer or an ultrasonic disintegrator. Ru,. Fill the crystalline suspension into 10 sterile vials of 1.01 tl vials at 5°C. The vials are frozen at -45°C, lyophilized in a lyophilizer, and then sealed.

b) Preparation of active drug suspension for parenteral administration (reconstitution) Injection into the contents of a nonoial containing 75 Mg of lyophilized diclofenac sodium (prepared as described in a) K above) at room temperature. Add 2.0 d of sterile water and shake to suspend the lyophilized drug. The suspension may be removed from the vial with a sterile syringe and then administered intramuscularly.

Example 2 a) Similar to the procedure of Example 1m) with 75 caps of diclofenac sodium and 100 eta of mannitol and 9 va
A lyophilized pharmaceutical formulation can be prepared containing y of NaCl. Alternatively, these lyophilized formulations can further contain 0.01 to 1011 P of Synberonic™.

b) According to the procedure of Example 1b), at room temperature, a lyophilized pharmaceutical formulation containing 75'q of diclofenac sodium is added to 0
．． 9-0 NaCl suspended in sterile water for injection 2, Od or 7519 diclofenac sodium, 50 IIF mannitol and 9/- NaCl
Sterile water for injection of lyophilized pharmaceutical preparation containing 2.0'
It is possible to suspend it in Itl.

Separately, these lyophilized pharmaceutical formulations also contain 0.01-10
The suspension can also be suspended by adding wq of Syn (Ronik™). The resulting isotonic suspension can be removed with a sterile syringe and administered intramuscularly.

Example 3 a) Preparation of a dry formulation (powder) Composition of each angle Preparation of 10 ampoules of Nidiclofenac 75 Cape: Lecithin was dissolved in 1011 tl of sodium chloride and the solution was passed through a membrane (pore size: 0.2 tan) by mouth. Ru,. 750y of micronized diclofenac sodium with an average particle size of less than 20 μm is added to the oral fluid and the resulting suspension is deagglomerated (see Example 1a). Remove the solvent under vacuum. Diclofenac sodium powder coated with lecithin, each vial containing diclofenac sodium 75%
Fill the vial with q.

b) Preparation of an Active Pharmaceutical Suspension for Parenteral Administration Following the procedure of Example 1m), the contents of a vial containing 75 cm of diclofenac sodium in the form of a lecithin-coated powder were mixed at room temperature with 0.9' Sterile water for injection with Ja NaCl2. Suspend in sterile water 2, Ojlj or an isotonic mixture of NaC2 and mannitol.

Example 4 a) Preparation of lyophilized pharmaceutical formulation Composition of each ampoule Nidiclofenac sodium 75 cape NaC 15,4
* Manitol 20m? Gruroec Preparation of 0.071910 ampoules 54.0q of sodium chloride (purified), 200q of mannitol and 0.7 of cape! Dissolve Ruronik in 7.0 ml of distilled water, and then pass the solution through a membrane filter (pore size: 0.2 μm) at approximately 120°C.
Sterilize in an autoclave.

Cool the sterile suspension to 5°C. Cooling solution K, 250
750 IIP of finely ground diclofenac sodium (purified) with an average particle size of less than am is added and the resulting suspension is deagglomerated, for example in a piston homogenizer or an ultrasonic disintegrator.

The crystalline suspension is filled at 5° C. into 10 sterile vials with a solution suitable for 0.8 P of material. 45 vials
Freeze at °C, lyophilize in a lyophilizer, and then seal.

b) Preparation of active drug suspension for parenteral administration (reconstitution) Injection of 1.0 d into the contents of a vial containing lyophilized diclofenac sodium (prepared as described in a) above) 7511F. Add sterile water at room temperature and then shake to suspend the lyophilized drug. The suspension can be removed from the vial with a sterile syringe and then administered intramuscularly.

Claims (1)

Claims: 1. A dry formulation for the preparation of a stable aqueous suspension of diclofenac in salt form, the formulation comprising a pharmaceutically acceptable and micronized salt of diclofenac as well as the desired and a pharmaceutically acceptable adjuvant. 2. The dry preparation according to claim 1 obtained by freeze-drying. 3. The dry preparation according to claim 1 or 2, which contains a diclofenac salt having an average particle size of less than 50 μm. 4. The dry preparation according to claim 3, which contains a diclofenac salt having an average particle size of less than 20 μm. 5. The dry preparation according to claim 3, which contains diclofenac sodium having an average particle size of less than 20 μm. 6. A method for preparing a dry formulation according to any one of claims 1 to 4, comprising the steps of: Said method comprising suspending the diclofenac salt and then removing the suspending medium. 7. The method of claim 6, wherein diclofenac salt in micronized form is suspended in an aqueous suspension medium containing isotonic components and the water is removed. 8. Suspending diclofenac salt in micronized form in an organic suspension medium containing phospholipids and removing the solvent;
Said method. 9. The dry preparation according to any one of claims 1 to 5, which is used in a method of treating a human or animal body. 10. The dry preparation according to any one of claims 1 to 5, which is used for the treatment of inflammatory conditions.