LT5696B - New combination of active ingredients containing a non steroidal antiimplamatotory drug and a colchicoside derivative - Google Patents

Abstract

Pharmaceutical cimposition containing a combination of a non steroidal anti inflamatory drug and a colchicoside derivative, the active ingredients being present in the free state or in the form of a salt.

Description

the present invention relates to a novel combination of a non-steroidal anti-inflammatory drug and a colchicoside derivative; pharmaceutical compositions comprising them for the alleviation and / or treatment of musculoskeletal and joint disorders such as ankylosing spondylitis, lower back pain, osteoarthritis and rheumatoid arthritis, and periarticular disorders such as bursitis and ligament inflammation; and the manner in which they are obtained.

Among these conditions, lower back pain (LBP) is a very common painful musculoskeletal disorder that virtually affects everyone at a certain time in their life and predominates in the 58% -84% range. Lower back problems are an important part of the reason for visiting clinics and require a great deal of medical treatment, loss of working capacity, and non-monetary costs such as disrupting the ability to practice and enjoy normal activities. Basically, for people over 45, lower back problems are the most common cause of incapacity.

Among the non-steroidal anti-inflammatory drugs known in the art that may be used in the present invention is ketoprofen. Ketoprofen or (RS) -2- (3-benzoylphenyl) propanoic acid is a non-steroidal anti-inflammatory drug. The anti-inflammatory, analgesic and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro systems. In anti-inflammatory models, ketoprofen exhibited inhibitory effects on prostaglandin and leukotriene synthesis, antibradykinin activity, and a stabilizing effect on the liposomal membrane. Ketoprofen can be synthesized by methods known in the art, such as those disclosed in U.S. Pat. No. 3,641,127 or FR2163875.

Of the known colchicoside derivatives known in the art that may be used in the present invention is thiocolchicoside. Thiocolchicoside or N- [1,2-dimethoxy-10-methylsulfanyl-9-oxo-3 - [(2S, 3R, 4S, 5S, 6R) -3,4,5-trihydroxy-6- (hydroxymethyl) -oxan-2-yl] oxy-6,7-dihydro-5H-benzo [d] heptalen-7-yl] -acetamide is a glucoside extracted from late spring seeds. It has muscle-relaxing, anti-inflammatory, analgesic and anesthetic effects with minimal side effects. The thiocolchicoside can be synthesized by methods known in the art, such as those described in FR1049755.

The active ingredients which form the combination are in free form or in the form of their salts.

These salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; salts with organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionic acid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, , lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid and salicylic acid; or salts with acidic amino acids such as aspartic and glutamic acid. Pharmacologically acceptable salts are preferred.

Another object of the present invention is a pharmaceutical composition comprising a combination of a non-steroidal anti-inflammatory drug and a thiocolchicoside, wherein both active ingredients are in free form or in salt form.

Another object of the present invention is a pharmaceutical composition comprising a combination of ketoprofen and thiocolchicoside wherein both active ingredients are in free form or in salt form.

Another object of the present invention is a pharmaceutical composition in a form adapted for oral administration.

Another object of the present invention is a pharmaceutical composition in solid dosage form.

Another object of the present invention is a pharmaceutical composition in the form of a thin film-coated tablet.

An advantage of the present invention is to provide a stable combination product having superior analgesic, anti-inflammatory and muscle relaxant properties over plain thiocolchicoside tablets. It also provides a combination product with reduced and controlled impurities.

The pharmaceutical composition and the process for its preparation include enabling the chemical interaction between thiocolchicoside and ketoprofen using pharmaceutically acceptable excipients in the form of a pharmaceutical. The cross-sectional data on impurities indicate that when ketoprofen and thiocolchicoside are mixed well with each other using pharmaceutically acceptable excipients, there is a significantly greater increase in the level of breakdown products compared to when they are present alone. The present invention relates to a pharmaceutical composition comprising ketoprofen and thiocolchicoside in free or salt form which is not well mixed in the composition.

In addition, the combination products exhibit increased and controlled contamination even less compared to thiocolchicoside tablets of the same dose in compression tests.

According to a more preferred embodiment of the invention, the active ingredients of the combination are ketoprofen and thiocolchicoside. the usual oral dose of ketoprofen is 50-100 mg twice daily. the usual starting dose of thiocolchicoside is 16 mg / day.

In the pharmaceutical compositions of this invention, the active ingredients are usually formulated in dosage units containing 50-100 mg ketoprofen and 4-8 mg thiocolchicoside per dosage unit.

Another object of the present invention is a pharmaceutical composition comprising 50 mg ketoprofen and 4 mg thiocolchicoside.

Another object of the present invention is a pharmaceutical composition comprising 100 mg ketoprofen and 8 mg thiocolchicoside

Another object of the present invention is a pharmaceutical composition comprising 100 mg of ketoprofen and 8 mg of thiocolchicoside in a solid solid dosage form.

The dosage and frequency of administration of the medicament of the present invention are not specifically defined and may be approximately selected depending upon features such as patient body weight or age, disease severity, and the like. Generally, the daily oral dose may be administered once daily or several times daily in divided doses or once daily.

According to other objects, the present invention relates to the use of a composition as described above for the manufacture of a medicament for the treatment of musculoskeletal and joint disorders such as ankylosing spondylitis, lower back pain, osteoarthritis and rheumatoid arthritis, and periarticular disorders such as bursitis and ligaments. alleviation and / or treatment of painful muscle spasms,

Another object of the present invention is a method of treating / alleviating the above pathologies, which comprises administering to the patient an effective amount of a composition of the present invention.

The pharmaceutical composition of the present invention may further comprise other active ingredients having acceptable pharmaceutical activity.

These compositions are preferably formulated for administration by the oral or parenteral route, and more preferably by the oral route.

For example, pharmaceutical compositions may be formulated, for example, in the form of pharmaceutical compositions for oral administration, such as granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions, and the like, or in the form of pharmaceutical formulations. for parenteral administration such as intravenous, intramuscular or subcutaneous injection, drip infusion, transdermal preparation, transmucosal preparation, nasal drops, inhalants, suppositories and the like. Injections or drip infusions may be formulated as powder formulations, such as lyophilized formulations, and may be used immediately prior to use in a suitable aqueous medium, such as saline.

Sustained-release formulations, such as polymer-coated formulations, may be directly administered intracerebral. Preferably, the pharmaceutical composition is in the form of a thin film-coated tablet.

The tablets may be coated with sugar or other suitable substances or, alternatively, may be formulated so as to exhibit sustained or delayed action and to provide continuous release of the active ingredient.

A gelatin capsule formulation is prepared by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. A known inert diluent such as water or a vegetable oil may be used to formulate the liquid compositions for oral administration. In addition to an inert diluent, the liquid composition may contain excipients such as wetting agents, suspension acids, sweeteners, flavoring coloring agents and preservatives. Liquid compositions may be filled into capsules made of an absorbent material such as gelatin. Formulations for parenteral administration, e.g. examples of solvent or suspension media for injection, suppositories, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate lecithin and the like. Examples of the basic materials used for suppositories include, for example, cocoa butter, emulsion-converted cocoa butter bay lipid, vitepsol.

Another object of the present invention is to provide a tablet dosage form comprising the steps of:

a) admixing ketoprofen and pharmaceutically acceptable excipients to obtain a mixed material;

b) obtaining a binder with pharmaceutically acceptable excipients,

c) adding a binder to a preparation containing ketoprofen,

d) wet granulation of the material obtained from c),

(e) wet formatting,

(f) drying,

(g) dry formatting,

(h) mixing the thiocolchicoside and the pharmaceutically acceptable excipients to form a blended material, sifting all the included materials through a 1 mm sieve,

(i) mixing material from steps (g) and (h);

(j) addition of a lubricant, sieving of all materials involved, with a 1 mm sieve

k) tableting to obtain a tablet formulation.

Another object of the present invention is a process for preparing a thin film film-coated tablet formulation comprising the preparation of a tablet formulation as described above followed by a heating and coating step to form a film coating of a thin film coated tablet. Another object of the present invention is a process for preparing a thin film film-coated tablet formulation comprising ketoprofen and thiocolchicoside without mixing them together.

The present invention is illustrated by the following examples which should not be construed as limiting the scope of the present invention.

example. Method of Preparation of Tablets Containing Ketoprofen and Thiocolchicoside Step: Ketoprofen is mixed with pharmaceutical excipients and mixed.

Step 1: Prepare the binding solution and granulate the Step 1 material to obtain uniform granules. The wet pellets were dried to achieve the optimum moisture needed for compression.

Step 1: The dry granules are sieved and thiocolchicoside with pharmaceutical excipients is added and mixed.

Step 4: Magnesium stearate is sieved and mixed.

Step 3: The mixture was compressed into tablets using appropriate embossing and coated with a coating material.

Alternatively, the tablets may be prepared by dry granulation, such as the following step: Ketoprofen is formulated with pharmaceutical excipients and mixed.

step; the content is compressed / compressed and sifted.

step; thiocolchicoside and other pharmaceutical excipients are screened and mixed.

step; the magnesium stearate is sieved and mixed.

Step 3: The mixture was compressed into tablets and coated using a coating material.

example: film-coated tablets containing 100 mg ketoprofen and 8 mg thiocolchicoside.

No. Ingredients QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) 1. Ketoprofen 100.00 100.00 100.00 100.00 2. Lactose monohydrate 367.60 340.50 321.75 253.00 3. Croscarmellose sodium (Ac di sol) 1.00 5.00 7.50 21.00 4. Corn starch 10.00 25.00 34.50 62.50 BINDING SOLUTION 5. Povidone K-30 1.00 3.25 4.10 10.50 6th Purified water how much do you need how much do you need how much do you need how much do you need EXTRAGRANULATE 7th Croscarmellose sodium (Ac di sol) 1.00 3.50 6.75 20.00 8th Colloidal silicon dioxide 0.40 0.75 0.90 3.50 9th Thiocolchicoside 8.00 8.00 8.00 8.00 10th Magnesium stearate 1.00 4.00 6.50 11.50 Weight of the tablet 490.00 490.00 490.00 490.00 11th CLOTHING 12th Yellow Opadry how much do you need how much do you need how much do you need how much do you need 13th Purified water how much do you need how much do you need how much do you need how much do you need Weight of the tablet 500.00 500.00 500.00 500.00

Example 3: Film-coated tablets containing 50 mg ketoprofen and 4 mg thiocolchicoside.

No. Ingredients QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) QYT (quantity) / TAB (mg) 1. Ketoprofen 50.00 50.00 50.00 50.00 2. Lactose monohydrate 183,800 170,250 160,875 126,500 3. Croscarmellose sodium (Ac d i sol) 0.5000 2,500 3,750 10,500 4. Corn starch 5,000 12,500 17,250 31,250 BINDING SOLUTION 5. Povidone K-30 0.500 1,625 2,050 5,250 6th Purified water how much do you need how much do you need how much do you need how much do you need EXTRAGRANULATE 7th Croscarmellose sodium (Ac d i sol) 0.500 1,750 3.375 10,000 8th Colloidal silicon dioxide 0.200 0.375 0.450 1,750 9th Thiocolchicoside 4,000 4,000 4,000 4,000 10th Magnesium stearate 0.500 2,000 3,250 5,750 Weight of the tablet 245,000 245,000 245,000 245,000 11th CLOTHING 12th Yellow Opadry how much do you need how much do you need how much do you need how much do you need Purified water how much do you need how much do you need how much do you need how much do you need Weight of the tablet 250,000 250,000 250,000 250,000

example: stability data (40 ° C / humidity factor

75%).

Pollution A Loti initial Lot 2 initial C Loti 40 ° C / 75% D Lot 2 40 ° C / 75% Unknown contamination 0.25 ND 0.27 ND Unknown contamination 0.47 ND 0.26 NC Unknown contamination 3 ND ND 1.17 ND Unknown contamination ND ND 1.14 ND Highest contamination 0.25 0.18 1.17 0.25 Total contamination 1.35 0.24 3.92 0.25

Column A: Lot 1 initial time containing ketoprofen and thiocolchicoside obtained by combined granulation.

Column B: Lot 2 initial time containing ketoprofen and thiocolchicoside obtained by extragranular granulation.

Column C: Lot 1 containing ketoprofen and thiocolchicoside, obtained by combined granulation after 2 months at 40 ° C / 75% RH. Contamination data are given in the table, measured at 40 ° C / Humidity at 75% RH 2M.

Column D: Lot 2 containing ketoprofen and thiocolchicoside obtained by extragranular granulation after 6 months at 40 ° C / 75% RH. Stability data indicate that Lot 1 (column A versus column C) is a significant increase in contamination level over 2 months at 40 ° C / humidity factor of 75% RH in the isolated sample. The stability data show that Lot 2 (column B before column D) shows no significant change in contamination even after 6 months at 40 ° C / 75% RH in the separated sample. From the above data it follows that when ketoprofen and thiocolchicoside are not completely mixed in the formulation, there is no significant interaction and the level of contamination is significantly lower.

Example: Safety and efficacy of a composition comprising ketoprofen and thiocolchicoside.

The composition of the present invention may be considered safe and effective in the treatment of severe lower back pain (LBP).

Claims (14)

A pharmaceutical composition comprising a combination of a non-steroidal anti-inflammatory drug and a colchicoside derivative, wherein the active ingredients are in free form or in salt form. Pharmaceutical composition according to claim 1, characterized in that it comprises a combination of a non-steroidal anti-inflammatory drug and a thiocolchicoside, wherein the active ingredients are in free form or in salt form. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises a combination of ketoprofen and thiocolchicoside, wherein the active ingredients are in free form or in salt form. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is in a form that can be administered orally. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is a solid dosage form. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is in the form of a film-coated tablet. Pharmaceutical composition according to any one of the preceding claims, characterized in that it comprises 100 mg of ketoprofen and 8 mg of thiocolchicoside and is presented in solid dosage form. 8. A pharmaceutical composition according to any one of the preceding claims, comprising 50-100 mg ketoprofen and 4-8 mg thiocolchicoside. 9. A pharmaceutical composition according to claim 8, comprising 100 mg ketoprofen and 8 mg thiocolchicoside. Pharmaceutical composition according to claim 8, characterized in that it comprises 50 mg of ketoprofen and 4 mg of thiocolchicoside. A pharmaceutical composition according to any one of the preceding claims for the treatment of musculoskeletal and joint disorders such as ankylosing spondylitis, lower back pain, osteoarthritis and rheumatoid arthritis, and for the treatment of periarticular disorders such as bursitis and ligament inflammation or painful muscle spasms. Use of a composition according to any one of the preceding claims for the preparation of a medicament for the treatment of musculoskeletal and joint disorders such as ankylosing spondylitis, lower back pain, osteoarthritis and rheumatoid arthritis, and periarticular disorders such as bursitis and inflammation of the muscles and for treatment or relief. 13. A process for preparing a tablet formulation comprising the steps of: a) admixing ketoprofen and pharmaceutically acceptable excipients to obtain a mixed material; b) obtaining a binder with pharmaceutically acceptable excipients, c) adding a binder to a preparation containing ketoprofen, d) wet granulation of the material obtained from c), (e) wet formatting, (f) drying, (g) dry formatting, (h) mixing the thiocolchicoside and the pharmaceutically acceptable excipients to form a blended material, sifting all the included materials through a 1 mm sieve, (i) mixing material from steps (g) and (h); (j) addition of a lubricant, sieving of all materials involved, with a 1 mm sieve k) tableting to obtain a tablet formulation. 14. A process for preparing a film-coated tablet formulation comprising the steps of providing a tablet formulation according to claim 13 followed by a heating and coating step to obtain a film-coated tablet formulation.