WO2004014431A1

WO2004014431A1 - A parenteral dosage form of selective cox-2 inhibitors

Info

Publication number: WO2004014431A1
Application number: PCT/IB2003/003219
Authority: WO
Inventors: Jyoti Srivastava; Ashish Sehgal; Vinod Kumar Arora; Rajiv Malik
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2002-08-12
Filing date: 2003-08-08
Publication date: 2004-02-19
Anticipated expiration: 2005-02-12
Also published as: AU2003249510A1

Abstract

The present invention relates to parenteral dosage forms of selective cyclooxygenase-2 (COX-2) inhibitory drugs and salts thereof. More particularly, the invention relates to a pharmaceutical dosage form of selective COX-2 inhibitors wherein the dosage form can be administered intramuscularly.

Description

A PARENTERAL DOSAGE FORM OF SELECTIVE COX-2 INHIBITORS

Technical Field of the Invention The present invention relates to pareiαteral dosage forms of selective cyclooxygenase- 2 (COX-2) inhibitory drugs and salts thereof. More particularly, the invention relates to a pharmaceutical dosage form of selective COIX-2 inhibitors wherein the composition can be administered intramuscularly.

Background- of the Invention Non-steroidal anti-inflammatory drugs (NSALDs) are widely prescribed as effective analgesics, antipyretic and anti-inflammatory agents. Their mechanism for action is based on their ability to inliibit prostaglandin synthesis, which is controlled by the enzyme cyclooxygenase. Cyclooxygenase exists in two isomers- COX1 and COX-2. COX-1 is present in most tissue-synthesized prostaglandins and is important in regulating cell function. It is responsible for most of the gastro-protective prostaglandin synthesis which is important in regulating cell function. COX-2 is generally undetectable in most tissues but increases its expression by 10-20 fold during acute inflarrαmation. Inhibition of COX-2 by NS AIDs would give an anti-inflammatory effect, whereas inliibition of COX-1 would result in adverse effects such as gastrointestinal toxicity and nephrotoxicity.

Selective COX-2 inhibitory drugs represent a major advance in the art. Among such drugs are substituted pyrazolyl benzenesulfonamides, substituted Isoxazolyl benzenesulfonamides and substituted (methyl sulfonyl)phenylfuranones. In particular, 4-[5- 4-methylphenyl) -3 -(trifluoromethyl)- lH-pyr azol- 1 -yl] -benzene sulfonamide, commonly known as celecoxib, 4-[5-methyl-3-phenylisoxazol-4-yl) benzene sulfonamide, commonly known as valdecoxib, 4-[4-(methylsulfonyl)phenyl]-3-phenyl-5h-furan-2-one, also referred to as rofecoxih, 4-[4-methylsulfonyι) phenyl]-2-cyclopenten-l-one, deracoxib and etoricoxib are relevant. Almost all of these COX-2 inhibitory drugs are only available in a variety of oral dosage forms.

Celecoxib was first described in US Patent No. 5,466,823 assigned to Searle. Celecoxib is commercially available as lOOrxig capsules to be administered twice a day for the treatment of osteo-arthritis and rheumatoid arthritis. No other dosage forms of celecoxib have been reported. ofecoxib was described in US Patent No. 5,474,995 assigned to Merck & Co. Rofecoxib is commercially available as 12.5 mg, 25 mg and 50 mg tablets to be administered once daily and as 12.5mg/5 ml or 25 mg/5 ml oral suspensions for the treatment of osteo-arthritis and the management of acute pain. Valdecoxib has been described in US Patent No. 5,633,272 assigned to Searle. It is marketed as 10 and 20mg tablets for treating symptoms associated with osteo-arthritis and rheumatoid arthritis.

Although oral administration is the most convenient and widely used route, it is associated with a delayed onset of the desired pharmacological action. It is known that mpon oral administration, the COX-2 inhibitors take approximately 3.0 hours for peak plasma concentrations to be achieved and have an onset of action 0.5 to 0.75 hours after administration. Additionally, the intake of food further influences drug absorption. However, acute pain, as in the case of arthritis and cancer, demands immediate relief. In. such cases, a parenteral route is more efficient and prompt, as compared to the oral route.

Parenteral routes of administration offer numerous benefits over oral delivery, A part from providing quicker onset of action, parenteral administration results in more predictable blood serum concentrations of the drug and losses in the gastrointestinal tract due to metabolism, binding to food and other causes are eliminated. For similar reasons, parenteral administration permits dose reduction. It is also the preferred method of drug delivery in emergency situations and is useful in non-cooperative patients.

Furthermore, COX-2 inhibitors have an oral bioavailability ranging from 80-85%_>, hence parenteral administration would bring about a reduction in the dose in comparison to oral dose.

Currently, the only available iηjectable dosage form comprising COX-2 inhibitors is parecoxib, a prodrug of valdecoxib. Parecoxib, when administered parenterally, is hydrolyzed to valdecoxib within the blood stream. It is commercially available as parecoxib sodium powder which may be reconstituted in a parenterally acceptable solvent liquid.

Pharmacia Corporation has filed a PCT Application, WO 02/080912, relating to parenterally deliverable formulations of water-soluble selective COX-2 inhibitory drugs and salts and prodrugs thereof. The invention describes dosage forms that are prepared as lyophilized powders for reconstitution. U.S. Patent No. 6,589,557, assigned to Acusphere, describes porous matrices of celecoxib with an enhanced rate of dissolution. The porous matrix may be reconstituted with an aqueous medium and administered parenterally.

Another PCT application WO 03/035063, describes a clear stable pharmaceutical preparation of selective COX-2 inhibitors preferably in the parenteral form. Those applicants assert that injectable formulations of COX-2 inhibitors can be obtained only when dissolved in a selective isosorbide type solvent.

COX-2 inhibitors have extremely low solubility in water, which is the main reason for preparing a reconstitutable powder composition. Due to limited chemical stability, it is preferable to reconstitute the composition within a short period of time before administration.

The process of developing stable parenteral dosage forms for selective COX-2 inhibitors is challenging for the pharmaceutical formulator because of low chemical and physical stability. Attempts have been made to formulate parenteral dosage forms for COX-2 inhibitors as lyophilized powders for reconstitution. An injectable solution composition prepared by reconstituting a powder composition in a parenterally acceptable solvent, preferably an aqueous solvent has limited chemical stability, in which case it is preferred to reconstitute the composition within a short period of time before administration. Moreover, lyophilized powders require increased handling and processing time. Furthermore, it requires costly and complex equipment.

Amongst all the parenteral routes known, i.e. intravenous, intramuscular, infra- arterial, subcutaneous, intraperitoneal, etc., intramuscular, is the most convenient and easily administrable routes. This route is considered less hazardous than the intravenous route.

Therefore, there is a need for stable parenteral dosage forms of COX-2 inhibitors which are available as clear solutions, ready for immediate administration.

Summary of the Invention In one general aspect there is provided a parenteral pharmaceutical dosage form comprising at least one selective COX-2 inhibitor dissolved in at least one non-aqueous protic solvent, other than isosorbide type solvent. This dosage form can be administered intramuscularly. Further, in this general aspect the dosage form my include various selective COX-2 inhibitors including celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib and parecoxib. The non-aqueous protic solvent of the dosage form comprises one or more of polyethylene glycol, polyvinylpyrrolidone, propylene glycol and glycerol.

hi this general aspect, the dosage form may also comprise co-solvents, for example ethyl alcohol and water. The dosage form may also comprise other pharmaceutically acceptable excipients, for example surfactants or solubilizers, preservatives and antioxidants. Suitable surfactants or solubilizers include polyoxyethylene sorbitan fatty acid esters and ethoxylated alcohols. Suitable preservatives include one or more of methylparaben, propylparaben and benzyl alcohol. Suitable antioxidants comprise one or more of ascorbic acid, alpha-tocopherol, ascorbyl palmitate, butylated hydroxy anisole and butylated hydroxy toluene.

hi another general aspect, the dosage form comprises the selective COX-2 inhibitor celecoxib at a concentration of about 1 mg to about 400 mg/ml.

In another general aspect, the dosage form comprises the selective COX-2 inhibitor comprises valdecoxib, at a concentration of about 1 mg to about 25 mg/ml.

In another general aspect, the dosage form comprises the selective COX-2 inhibitor comprises rofecoxib at a concentration of about 1 mg to about 25 mg/ml.

In yet another general aspect, there is provided a process for preparing a parenteral pharmaceutical dosage form of selective COX-2 inhibitors comprising dissolving the COX-2 inhibitor in a non-aqueous protic solvent, sterilizing the solution, and filling the solution into ampoules or vials. The dosage form- may further comprise co-solvents and pharmaceutically acceptable excipients. Suitable sterilization techniques include aseptic filtration, autoclaving, steaming or irradiation, hi the preferred embodiment, aseptic filtration is utilized.

In a final general aspect, there is provided a method of treating or preventing COX-2 mediated disorders in a human subject, comprising administering a parenteral pharmaceutical dosage form comprising at least one selective COX-2 inhibitor dissolved in at least one non- aqueous protic solvent. In this embodiment, the parenteral administration comprises intramuscular injection.

Detailed Description of the Invention Herein is provided an injectable formulation of selective COX-2 inhibitors that is stable, clear and cost -effective to obtain.

The pharmaceutical dosage form of the present invention comprises at least one therapeutic agent selected from selective COX-2 inhibitory drugs and at least one non- aqueous protic solvents other than isosorbide type solvents.

Selective COX-2 inhibitory drugs include those drugs, prodrugs or salts of drugs which exhibit selective inhibition of COX-2, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, parecoxib and deracoxib.

The term "non-aqueous protic solvent" means a non-aqueous solvent which contains hydrogen attached to oxygen or nitrogen so that it is able to form hydrogen bonds or donate a proton. The solvents used in the parenteral dosage forms should be non-irritating, non-toxic, non-sensitizing, should not have pharmacological activity of its own and should not affect the activity of the drug. Examples of non-aqueous protic solvents are polyvinylpyrrolidone (PNP), polyethylene glycols (PEGs), propylene glycol (PG) and glycerol.

The term "chemical stability" means that an acceptable percentage of degradation products produced by chemical pathways, such as oxidation or hydrolysis, is formed. In particular, a formulation is considered chemically stable if it passes a standard test for chemical purity of the therapeutic agent, as may be required for approval by a regulatory authority.

It is another general aspect to provide a process for the preparation of an intramuscular injectable dosage form such that it delivers to the systemic circulation a dose ranging from about 10 to about 400mg/ml and has low toxicity as shown by the toxicity studies reported herein. The process for the preparation of the injection dosage forms of the present invention involves the dissolution of the active ingredient in a suitable non aqueous protic solvent. Apart from the drug and the solvent, the pharmaceutical dosage forms may optionally comprise co-solvents such as ethyl alcohol and water. The pharmaceutical dosage forms may optionally comprise pharmaceutically acceptable excipients such as surfactants or solubilizers, preservatives and antioxidants. Suitable surfactants or solubilizers may comprise one or more of polyoxyethylene sorbitan fatty acid esters and ethoxylated alcohols. Suitable preservatives may comprise one or more of methylparaben, propylparaben and benzyl alcohol. Suitable antioxidants may comprise one or more of ascorbic acid, alpha- tocopherol, ascorbyl palmitate, butylated hydroxy anisole and butylated hydroxy toluene.

hi all cases, the final dosage form must be sterile and stable. Techniques such as aseptic filtration, autoclaving, steaming and irradiation may be used for sterilization.

Compositions of the invention are useful in the treatment and prevention of a wide range of disorders in humans mediated by COX-2, including but not restricted to disorders characterized by inflammation, pain and or fever. Such compositions are especially useful as anti-inflammatory agents, such as in treatment of arthritis, with the additional benefit of having significantly less harmful side effects than compositions of conventional NSAIDs that lack selectivity for COX-2. In particular, the dosage forms of the present invention have a reduced potential for gastrointestinal toxicity and irritation, including upper gastrointestinal ulceration and bleeding, by comparison with compositions of conventional NSAIDs. Thus, the dosage forms of the invention are particularly useful as an alternative to conventional NSAIDs where NSAIDs are contraindicated.

Such dosage forms are useful in the treatment of pain, including but not limited to postoperative pain, dental pain, muscular pain, and pain resulting from cancer. Particularly, the dosage forms are used for the treatment of rheumatoid arthritis and osteoarthritis, for pain management, for treatment of Alzheimer's disease, and for colon cancer chemoprevention. Besides being useful for human treatment, compositions of the invention are useful for veterinary treatment of animals, particularly mammals.

The present invention is further directed to a therapeutic method of treating a condition or disorder where treatment with a COX-2 inhibitory drug is indicated, the method comprising parenteral administration of the dosage form of the invention to a subject in need thereof. The dosage regimen to prevent, give relief from, or ameliorate the condition or disorder preferably corresponds to once-a-day or twice-a-day treatment, but can be modified in accordance with a variety of factors. These include the type, age, weight, sex, diet and medical condition of the subject and the nature and severity of the disorder. Thus, the dosage regimen actually employed can vary widely and can therefore deviate from the preferred dosage regimens set forth above.

The following examples illustrate various aspects of the present invention. These examples are for illustration only and should not be construed as limiting the scope of the invention.

EXAMPLE 1

PEG 400 and propylene glycol (65% of the total) were added to Pure Anhydrous Ethyl Alcohol in a dry vessel and the solution was stirred to get a clear solution. Celecoxib was dissolved in this solution followed by the addition of benzyl alcohol and the volume was made up with propylene glycol. The solution was filtered through 0.2-micron filter and filled into 3 ml clear glass ampoules.

The intramuscular injectable formulation made in accordance with example 1 was subjected to sub chronic intramuscular toxicity study in Swiss albino mice. Celecoxib injections were administered to mice via intramuscular route at dose levels ranging from 0 g/kg to 200mg /kg body weight and the results of the study showed that:

(i) Male and female animals from different dose groups survived the dosing period of

14 days, (ii) Hematological analysis revealed no abnormalities attributable to treatment. (iii) Biochemical analysis revealed no abnormalities attributable to the treatment. (iv) Urine analysis revealed no abnormalities attributable to the treatment.

(v) Gross pathological examination revealed focal necrosis at the site of injection from control as well as all treatment dose groups, (vi) Histopathological examination revealed minimal focal necrosis at the site of injection in control and all treatment dose groups, (vii) Food intake of animals from control and different dose groups was found to be comparable throughout the dosing period of 14 days, (viii) Three male and three female animals treated at the dose level of 200mg / kg exhibited reduced locomotor activity during the dosing period of 14 days.

Animals from 50mg/kg and lOOmg / kg dose groups exhibited no signs of intoxication throughout the dosing period of 14 days.

Based on these findings the "no observed effect level" (NOEL) of celecoxib injection 100 mg/ml (3.0 nxl) when admimstered to Swiss Albino mice via intramuscular route over a period of 14 days was found to be about lOOmg /kg in male and female animals.

An accelerated stability study was performed on celecoxib inframuscular solution prepared according to Example 1 (and sterilized by aseptic filtration) for 3 months at 40°+2°C and 75+5% relative humidity. The results of the study are presented in Table 1.

Table 1 : Accelerated stability studies of celecoxib intramuscular solution at 40°±2°C and 75±5% relative humidity

EXAMPLE 2

A slurry (10%w/v) of rofecoxib was made in water for injection and it was nanonised to a particle size of less than 1.0 micron for rofecoxib. Polyethylene glycol 400 was added under stirring to a nanonised slurry of rofecoxib till it dissolved completely. To this bulk, polyoxyethylene sorbitan ester was added and was stirred continuously to get a clear solution. Benzyl alcohol was added to this solution and stirred till it mixes completely. The volume was made up with polyethylene glycol 400. The solution was filtered through 0.2-micron filter and filled into 3.0 ml clear glass sterile USP Type-I ampoules.

EXAMPLE 3

Procedure:

1. Polyethylene glycol 400, Pure Anhydrous Ethyl Alcohol and a portion of propylene glycol were stirred to mix completely.

2. Valdecoxib was added to the bulk of step 1 under constant stirring till it solubilizes completely.

3. Water for injection was added to the bulk of step 2 under constant stirring.

4. Benzyl alcohol was added to the bulk of step 3 under constant stirring to mix completely.

5. The volume was made up with propylene glycol. 6. The solution of step 5 was filtered through 2.0 / 0.2 μ nylon membrane filter and filled in 2 ml clear glass vials (USP Type I) and sealed with rubber stopper and aluminum seal.

AJI accelerated stability study was performed on the valdecoxib intramuscular solution prepared according to Example 3 (and sterilized by aseptic filtration) for 3 months at 40°+2°C and 75+5% relative humidity. The results of the study are presented in Table 2.

Table 2: Accelerated stability studies of valdecoxib intramuscular solution at 40°±2°C and 75+5% relative humidity

EXAMPLE 4

Procedure: Similar to Example 3

EXAMPLE 5

Procedure: Similar to Example 3

While several particular forms of the invention have been illustrated and described, it will toe apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

WE CLA :

1. A parenteral pharmaceutical dosage form comprising at least one selective COX-2 inhibitor dissolved in at least one non-aqueous protic solvent, wherein the non- aqueous solvent is not an isosorbide type solvent.

2. The dosage form according to claim 1 wherein the dosage form is administered intramuscularly.

3. The dosage form according to claim 1 wherein the selective COX-2 inhibitor comprises one or more of celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib and parecoxib.

4. The dosage form according to claim 1 wherein the non-aqueous protic solvent comprises one or more of polyethylene glycol, polyvinylpyrrolidone, propylene glycol and glycerol.

5. The dosage form according to claim 1 furthier comprising one or more co-solvents.

6. The dosage form according to claim 5 wherein co-solvent comprises one or more of ethyl alcohol and water.

7. The dosage form according to claim 1 furthier comprising one or more pharmaceutically acceptable excipients.

8. The dosage form according to claim 7 wherein the one or more pharmaceutically acceptable excipients comprise surfactants or solubilizers, preservatives and antioxidants.

9. The dosage form according to claim 8 wherein the surfactants or solubilizers comprise one or more of polyoxyethylene sorbitan fatty acid esters and ethoxylated alcohols.

10. The dosage form according to claim 8 wherein the preservatives comprise one or more of methylparaben, propylparaben and benzyl alcohol.

11. The dosage form according to claim 8 wherein the antioxidants comprise one or more of ascorbic acid, alpha-tocopherol, ascorbyl palmitate, butylated hydroxy anisole and butylated hydroxy toluene.

12. The dosage form according to claim 3 wherein the selective COX-2 inhibitor comprises celecoxib.

13. The dosage form according to claim 12 wherein the concentration of celecoxib comprises about 1 mg to about 400 mg/ml.

14. The dosage form according to claim 3 wherein the selective COX-2 inhibitor comprises valdecoxib.

15. The dosage form according to claim 14 wherein the concentration of valdecoxib comprises about 1 mg to about 25 mg/ml.

16. The dosage form according to claim 3 wherein the selective COX-2 inhibitor comprises rofecoxib.

17. The dosage form according to claim 16 wherein the concentration of rofecoxib comprises about 1 mg to about 25 mg/ml.

18. A process for preparing a parenteral pharmaceutical dosage form of selective COX-2 inhibitors comprising: i. dissolving the COX-2 inhibitor in a non-aqueous protic solvent, wherein the solvent is not isosorbide; ii. sterilizing the solution; and iii. filling the solution into ampoules or vials.

19. The process according to claim 18 wherein the dosage form further comprises co- solvents.

20. The process according to claim 18 wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.

21. The process according to claim 18 wherein sterilization comprises one or more of aseptic filtration, autoclaving, steaming or irradiation.

22. The process according to claim 21 wherein sterilization comprises aseptic filtration.

23. A method of treating or preventing COXI-2 mediated disorders in a human subj ect, comprising administering a parenteral pharmaceutical dosage form comprising at least one selective COX-2 inhibitor dissolved in at least one non-aqueous protic solvent, wherein the protic solvent is not isosorbide.

24. The method of claim 22, wherein the parenteral administration comprises intramuscular injection.