IE60453B1

IE60453B1 - Parenteral suspensions of diclofenac

Info

Publication number: IE60453B1
Application number: IE25088A
Authority: IE
Inventors: J J Peter Glanzmann; Leo Geller
Original assignee: Ciba Geigy Ag
Priority date: 1987-01-30
Filing date: 1988-01-29
Publication date: 1994-07-13
Also published as: ZA88638B; AU1110288A; FI880368A0; ES2008420A6; DK45588A; DK45588D0; NO880403D0; MY102662A; NO880403L; FR2611498B1; BE1000442A4; GB2201089A; SE8800228D0; CH673395A5; GR880100041A; JPS63192716A; SE8800228L; IT8847557A0; ATA18588A; AU612343B2

Abstract

A dry formulation, in particular obtainable by lyophilisation, which is suitable for the preparation of a stable, aqueous suspension for the parenteral administration of a diclofenac salt contains a pharmaceutically acceptable and micronised salt of diclofenac and optional pharmaceutically acceptable adjuvants.

Description

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 th* parenteral administration of a diclofenac salt, to the use of said formulation for the preparation of a stable aqueous suspension containing said diclofenac salt.

Various medicaments of different structure are available for th® treatment of inflammatory diseases, a.g. rheumatism. As the course inflammations take is often chronic, it is usually nseessary to 0 carry out the treatment with antiinflammatory drugs over a prolonged period of time without interruption. Ia particular, many nonsteroidal antiinflammatory drugs (NAIDS), when administered orally, can cause disorders in th® entire gastrointestinal tract, especially gastric ulcers.

The sodium salt of diclofenac, available under the trademark Voltaren (Ciba-Geigy), belongs to the group of nonsteroidal antiinflammatory drugs of the first isportane®.

To enhance drug safety, there is a need te provide novel parenteral dosage forms for diclofenac and the salts thereof 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 effect*.

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 generally9 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„ SL. Voigt, Lehrhuch der Pharmazeutischen Teehnologie, Verlag Chemie, p. 383, 19.5.1.2.1). Consequently, there is also a need for suspen10 sions containing a diclofenac salt, in particular diclofenac sodium, for substantially pain-free intramuscular administration.

The above objects of th® invention are achieved by means of the present invention, which relates to a dry formulation containing a diclofenac salt in micronised forts 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 th· 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-(2,6-dichloro25 anilino)phenylacetic acid, is in particular an alkali metal salt, e.g. the sodium or potassium salt, er a salt with as amine, e.g. a eon©-, di- er trialkylaaine containing 1 te 4 carbon atoms in th* alkyl moiety or moieties, e.g. diethylamine or triethylamine, hydroxyalkylamine containing 2 to 4 carbon atoms in the alkyl aoiety, e.g. ethanolamine, hydroxyalfcylalkylamiae containing 2 to 4 and 1 to 4 carbon atoms respectively in each of the alkyl moieties, e.g. dimethylethanolamins„ or a quaternary ammonium salt, e.g. th® tetramethylasaaionius salt or choline salt of diclofenac.

Particularly preferred salts of diclofenac are th© sodium and potassium salts (q.v. Merck Index, Tenth Edition, No. 3066).

The dry formulation of this invention contains th® diclofenac salt, in particular th© sodium or potassium salt of diclofenac, in micronised form.

The micronised diclofenac salt has a preferred average particle size smaller than 50 pm, preferably smaller than 20 pm. Particles of this site are obtained hy conventional coaainution methods* e.g. grinding ia aa air jet sill* ball mill er vibratos mill. Hlcronisatioa is preferably effected by per se known methods using an ultrasonics disintegrator, e.g. of the Branson Senifier type as described e.g. in J. Pham. Sci. 53 (9), 1040-1045 (1965), or by stirring « suspension with a high-speed agitator, for example with a stirrer of th© Homorex type (supplied, by Brogli fis 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. eethanol, ethanol or propylene glycol, and precipitating it in microcrystalline form ac ca. 0^-5^0 ia water or aa aqueous salt solution, e.g. 2 % sodium chloride solution which nay additionally contain a protective colloid such as gelatin er a cellulose ether, e.g. methyl cellulose or hydroxypropyl methyl cellulose, la 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, preferably at 0.5 ebar). The subsequent drying can be effected at ca. 50e-90°C.

Pharmaceutically acceptable adjuvant# which the dry formulation say contain are e.g. ionic isotonic components such a# sodium chloride, or nonionic components, especially builders, such as sorbitol. mannitol or glucose. Preferably the dry formulation contain® these adjuvants, e.g. sodium chloride or mannitol, in th® 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 (lecithin), phosphatidyl ethanolanine (eephalin), phosphatidyl serine, phosphatidyl liaositol or mixtures of these lipids.

Preferred phospholipids are, for example, soybean or egg lecithin, or soybean or egg eephalia in pharmaceutical purity, or mixtures of phospholipids of different phosphatidyl choline content approved for pharmaceutical use. e.g. ’mixtures of lecithins which rare commercially available under the trademarks Epikuron 145, 170 or 200 (Lucas Heyer, Samburg) or Lipoid 45, 80 os 100 (Lipoid KG, Mannheim)The cited phospholipids may be present ia the solid formulation ia weight ratio» of active drug to phospholipid of Is0.1 tc 1:1, preferably from 1:0.1 to 1:1.

Further suitable adjuvants ia the dry formulation are wetting agents useful for liquid pharmaceutical formulation· or true surfactants, In particular nonieaic surfactants of the fatty acid polyhydroxy alcohol aster type such a® sorbitan uonolaurate, aonooleate, monostearate ©r nonopalmitate,, sorbitan tristearate or trioleate, adduct» of polyoxethyleae and fatty acid polyhydroxy alcohol esters such a® polyoxyethylene sorbitan Esaolaurate, anoaooleate, aosostearate, eonopalmitate, tristearate or trioleate,, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, polyethylene glycol 2000 stearate, in particular ethylene oxide/prepylene oxide block polymers of the Plutonic» type (syandotts) or Synperonic (ICI).

**(Trade Mark) *(Registered Trade Mark) These surfectants may he present in the dry formulation in weight ratios of active drug to surfactant of 1:1.0 x 10 ' to 1:0-1, preferably off 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 os adjuvants, such as sodium chloride, mannitol or glucose, which ate 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 caa be effected by known methods of lyophilisation, e.g. normally by filling a specific amount of the prepared suspension into suitable containers such as aapculea„ e.g. vials,» sad thereafter freezing the filled vials at ca- -40® to -50*C, preferably at -45*C, and then carrying out lyophilisation under a pressure of ca. 0.OS to 0-6 mbar by slowly warming to a final temperature ©ff .aa- 25^-55^0.

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, ©ethanol, ethanol or methylene chloride, and the micr©nised salt is suspended in this solstios. After stripping off the organic solvent,, the dry formulation coated with the adjuvant, such as a phospholipid, is filled is 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 lyophilised formulations, and suspensions that can bs reconstituted therefrom and which are stable and suitable for injection.

The use of ch© dry formulations obtainable by th© process of this invention for the preparation of injection suspensions iss also an object ox this invention. These injection suspensions can be administered as injection formulations parenterally. preferably intramuscularly. 0 The dry formulation of this invention is reconstituted, prior to adaiaistration, as a suspension in the proscribed amount of liquid, ©specially sterilised (pyrogen-free) water for injection, A hoaogeneous suspension of the previously aieroniaed drug ls formed once more by shaking. Instead of a dry formulation containing tine diclofenac salt and th® water-soluble adjuvants such as sodium chloride as mannitol, it is alsc possible to suspend a. dry formulation containing only the diclofenac salt (without adjuvants) in the prescribed aeount of liquid containing the cited water-soluble adj swaafcs» The particle sire of the aicroaised drug reaains unchanged during the preparation of th© suspension. Thus no noticeable crystal growth» e-g- resulting from hydrate fcreation, is observed in the suspension to be adainistered. The suspension of the drug also has th© advantage that it does not adhere to the wail of the ampoule and can be readily and completely withdrawn free the aepoule with the syringe. A particularly preferred embodiment of the invention comprises preparing injection suspeasicB* that contain the customary doses of SO». 75 or 100 sg of diclofeaas sodium, having a total volume of 1.0 to 3.0 sal, preferably of 2.0-1.0 ml. especially a 0 voluos of 1.0 «1.

These suspensions can be used as ready for as® formulations.

The present invention relates in particular to dry formulations and to che us® thereof for the preparation of sn aqueous suspension for the intramuscular administration of diclofenac sodium. Th© dry formulation and the suspension preferably contain micronised diclofenac sodium having ss average particle sire smaller than 20 pss and optional adjuvants such as sodium chloride, mannitol, sorbitol as well as lipids such as lecithin or wetting agents of the SYNPERONTG or PLURONIC typeThe suspensions of this Invention can be used for parenteral (intramuscular) formulations for the treatment o£ painful conditions» inflammations and/or rheumatic 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 th© customary amounts of drug of e.g. 25» 50, 75, 100 or Ϊ50 rag.

The following Examples illustrate the invention, but imply n© restriction to what ia described therein. jSxaatple 1 s a) Preparation of the lyophilised, drug formulation Composition ox each ampoule: diclofenac sodium 75 rag Had IS ag Preparation of 10 ampoules: 180 eg of sodium chloride (puriss.) ere dissolved ia 10 ml of distilled water end the solution Is filtered through a membrane filter (pore sices 0.2 μ») and sterilised» e.g. ia a© autoclave at ca. 120°C. The sterilised sodium chloride solution is cooled to S^C. To the cooled solution are added 750 ag of micronised diclofenac sodium (puriss.) having an average particle size smaller than 20 pta and the resultant suspension i® deagglomerated, e.g- in a piston homogeniser ©r ultrasonics disintegrator. The crystalline suspension ie filled at 5°C into 10 sterilised vials of 1.0 ml volume. The vials ar® frozen at -45°C. lyophilised in a frees® drying apparatus ' and then sealed. '1 b) Preparation of the active drug suspension for parenteral administration (reconstitution) To th® contents of a vial containing 75 mg of lyophilised 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 with1 0 drawn from the vial with a sterilised syringe and can be administered intramuscularly.

Example 2s 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 alse additionally contain 0.01 t«j 10 ag of Synperonic » b) Following the procedure of Example lb), it is possible to suspend, at rear temperature» lyophilised drug formulations con20 t&ining 75 mg of diclofenac sodium ia 2.0 al of sterilised water for injection which contains 0.9 * of NaCl, os lyophilised drug formulations containing 75 ag of diclofenac sodium and IGG ag of mannitol, or 75 mg of diclofenac sodium, 50 eg ©£ mannitol and S' mg of NaCl in 2.0 ml of sterilised water for injection. Alternatively, these lyophilised drug formulations can also he suspended with the addition of 0-01 to 10 sg of Synperonic . The isotonic suspensions so obtained can be withdrawn by a sterilised syringe and administered intramuscularly. ο Example 3: a) Preparation of the dry formulation (powder) Composition of each ampoule: diclofenac 75 ng / lecithin (Epikuron. 145, 170 or 200) 2-20 rag Preparation of 10 ampoules: The lecithin is dissolved in 10 »1 of methylene chloride and the solution is filtered through a, membrane (pore size: 0,,2 pa). To the filtered solution ar® added 750 mg of micronised diclofenac sodium having an average particle size smaller than 20 pm, and the suspension so obtained is deagglomerated (q.v. Example la). The solvent is then removed under vacuum. Th© diclofenac sodium powder coated with lecithin is filled into vials such that each contains 75 mg of diclofenac sodium. b) Preparation of the .active dya% suspension for parenteral administration Following the procedure of Example la), the contents of a vial containing 75 sag of diclofenac sodium in the fora of the lecithincoated powder are suspended at ro®® temperature ia 2.0 ssl of sterilised water for injection which contains 0.9 % of NaCl or ia 2,0 al of sterilised water which contains aa isotonic mixture of NaCl and mannitol.

Example 4 s a) Preparation of the lyophilised drug formulation 25 Composition of each ampoule: diclofenac s©di«E 75 ag NaCl 5.4 sag mannitol 20 ag FLURONTC 0.07 ag "ί n Preparation of 10 ampoules: 54.0 sag of sodium chloride (puriss.)5 200 mg mannitol and 0,7 ag PLUR0N1C are dissolved in 7.0 ml of distilled water and th® solution is filtered through a membrane filter (pore size: 0.2 μ®) and sterilised, e.g. in an autoclave at ca. 120"C. The sterilised suspending agent is cooled to 5eC. To th® cooled solution ar® added 750 mg of mieronised diclofenac sodium (puriss.) having an average particle size smaller than 20 pm and the resultant suspension is deagglomerated, e.g. in s piston homogeniser or ultrasonics disintegrator. Th© crystalline suspension is filled at 5®C into 10 sterilised vials of a volume suitable for 0.8 g substance. The vials are frozen at -45*C, lyophilised in a freeze drying apparatus and then sealed. 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 roasi temperature, 1.0 al of sterilised water fos injection and the lyophilised drug is suspended hy shaking. The suspension is withdrawn from, the vial with a sterilised syringe and can be administered intramuscularly.

Claims

1. CLAIMS;

1. A dry formulation for th® preparation of a stable, aqueous suspension of diclofenac in salt form, which formulation contains a pharmaceutically acceptable and micronised salt of diclofenac and 5 optional pharmaceutically acceptable adjuvants.

2. A dry formulation according to claim 1 when obtained 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 pm. 10

4. , A dry formulation according te claim 3» which contains & diclofenac salt having an average particle size smaller than 20 pm.

5. A dry formulation according 'to claim 3, which contains diclofenac sodium having an. average particle sise smaller than 20 pig.

6. A process for the preparation of a dry formulation according to 15 any one of claims 1 is 4, which comprises suspending a diclofenac salt in micronised form in a suspending medium which contains th© optional pharmaceutically acceptable adjuvants, and removing said suspending medium.

7. A process according to claim 6», which comprises suspending the 20 diclofenac salt in micronised forra is. an aqueous suspending medium which contains isotonic components and removing th® water.

8. A process according to claim 6, which comprises suspending the diclofenac salt in micronised fora in an organic suspending medium which contains phospholipids and removing the solvent. 1 3

9. Use of a dry formulation according to any one of claims 1 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 5 adjuvants.

10. A dry formulation according to any one of claims 1 to 5 for us® in a therapeutic method of treating the human or animal body. Π. A dry formulation according to any one of claims 1 to 5 for use in the treatment of inflammatory conditions. 10 12. A dry formulation according to claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

11. 13. A process for the preparation of a dry formulation according to claim 1, substantially as hereinbefore 15 described with particular reference to the accompanying Examples.

12. 14. A dry formulation according to claim 1 g whenever prepared by a process claimed in a preceding claim.

13. 15. Ose according to claim S', substantially as herein20 before described.