WO2009065604A2

WO2009065604A2 - Pharmaceutical composition comprising glucosamine sulfate, chondroitine sulfate and ibuprofene

Info

Publication number: WO2009065604A2
Application number: PCT/EP2008/009897
Authority: WO
Inventors: Anna Bozhek
Original assignee: Bayer Consumer Care Ag
Priority date: 2007-11-23
Filing date: 2008-11-21
Publication date: 2009-05-28
Also published as: EA019542B1; WO2009065604A3; EA201000810A1

Abstract

The present invention relates to the field of medicine and, more particularly, to drugs for internal use to treat a pain syndrome during a pain exacerbation phase in primary osteoarthrosis and secondary osteoarthrosis and other degenerative dystrophic diseases of extremity joints and intervertebral disks. The pharmaceutical composition for oral administration comprises chondroitin sulfate salt and glycosamine sulfate salt, ibuprofen as a nonsteroidal anti¬ inflammatory drug, and auxiliary substances wherein the ingredients are comprised in the following ingredient ratio (% w/w): Chondroitin sulfate salt 20 to 30 Glucosamine sulfate salt 30 to 36 Ibuprofen 10 to 15 and auxiliary substances Q. S. The present invention provides a pharmaceutical composition which ensures a chondroprotective, anti-inflammatory, and analgetic effect, an effective treatment of degenerative dystrophic diseases of extremity joints and intervertebral disks, a convenience of using the medicine, decrease in side effect risks, and the provision of an alternative medicament.

Description

A pharmaceutical composition

The present invention relates to the field of medicine and, particularly, to drugs for internal use to treat a pain syndrome during a pain exacerbation phase in primary osteoarthrosis and secondary osteoarthrosis and other degenerative dystrophic diseases of extremity joints and intervertebral disks.

Currently, joint diseases are one of the most frequent causes of seeking medical attention. Joint diseases are caused by incompletely cured traumas or microtraumas, metabolic and immune disorders in the body, ligament ruptures, blood supply disturbances in a bone and cartilage tissue, in particular, hard physical work, as well as overweight. Heavy loads on the joints associated with some or other occupations also result in the development of joint diseases. An athletic overload is also a factor of risk. Various infections that lead to an acute inflammation of the joints (reactive arthritis) are also dangerous for the joint cartilage. Arthrosis is one of the chronic joint diseases of a metabolic nature, which is accompanied by changes in the mating surfaces of bones. Arthrosis can occur as a result of intoxications, infectious diseases (for example, typhus, syphilis, etc.), various traumas of joints (a joint bone end fracture, a damage of the joint cartilage) and also as a result of functional joint overload (for example, of ballet dancers, loaders, etc.) Osteoarthrosis (OA) is a chronic progressive degenerative joint disease characterized by the degradation of joint cartilage with subsequent changes in the subchondral bone and with the development of marginal osteophytes leading to the loss of cartilage and a concomitant damage of the other joint components (synovial membrane, filaments). Osteoarthrosis is the most widespread type of joint pathology. In the Western Europe countries, radiological signs of OA are found in most people above 65 and in around 80% of people above 75. Around 11% of people above 60 have a symptomatic (with clinical manifestations) OA of the knee joints. Among the Americans above 30, a symptomatic OA of the knee joints occurs in around 6%, and a symptomatic OA of the hip joints occurs in around 3% of the population. Owing to its prevalence and a frequent disability which accompanies this disease if sited in the knee joint and hip joint, OA causes the largest number of problems connected with walking and going upstairs as compared with any other disease. Though the development of OA does not affect a prognosis for the life, this disease is one of the root causes of early disability and invalidity as well as of a chronic pain syndrome, which deteriorate significantly the quality of life of elderly and old people. Due to a substantial senescence of population, the problems of prevention and treatment of this disease are becoming especially urgent.

To reduce inflammation and pain syndrome during an acute period of the diseases, two groups of medications are widely used in traditional medicine: nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids (or corticosteroids, steroids, steroid hormones). The medications of the first group are widely known; these include aspirin, ibuprofen, diclofenac, among many others. Many of these medications have, however, serious side effects such as gastrorrhagia, gastric ulcer, stomach wall perforation, bronchiospasms, allergies, etc. The medications of the second group, glucocorticoids, contain natural hormones of the adrenal cortex or synthetic substances ciose thereto in effect. They include prednisolone, dexometasone, triamcinolone, cortisone, and some other hormonal preparations. Glucocorticoids are highly efficient medications capable of inhibiting an inflammatory response. But they are only used when other medicines do not avail, for they are characterized by a multitude of side effects affecting substantially all of the body systems. Currently, thus, the question is not whether side effects will occur or not but rather when they will occur. This in turn depends directly on the frequency of administration and dosage of medicines. As a rule, after a long-term administration of a drug, drug addiction develops and, as a consequence, its dosage should be increased. This, certainly, affects the occurrence of side effects. Thus, development of a medicine, which is effective in the treatment of degenerative dystrophic joint diseases and causes no serious side effect owing to decrease in medicine dosage, is a topical problem nowadays.

The closest prior art of the claimed invention is a pharmaceutical composition that is disclosed in the Ukrainian patent No. 78917 which pharmaceutical composition comprises chondroitin sulfate and glycosamine sulfate salt, ibuprofen as a NSAID, and auxiliary substances. At the same time, as a chondroitin sulfate salt there is used sodium, potassium, or calcium salt thereof, and glycosamine hydrochloride, sodium, potassium, or calcium salt of glycosamine sulfate is used as a glycosamine sulfate salt. As the NSAID, the pharmaceutical composition may contain nimesulide or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen. In addition, the pharmaceutical composition contains dimethyl sulfoxide and an ointment base.

A disadvantage of the composition above is the use of this medicine in the form of ointment that makes it difficult to ensure the maximum dispersion of the pharmaceutical substance over the entire volume of the ointment to achieve the desired therapeutic effect and dosage accuracy. Furthermore, ointments often impair the physiological functions of the skin for an initial pH of the skin changes and a decrease in the activity of pharmaceutical substances is possible. This leads to the necessity to increase in the dosage of the medicine, which in turn increases side effect risks. Moreover, ointment is a topical dosage form, this not always allowing the desired effect to be achieved; also, the use of ointment may be connected with certain inconveniences in application and absorption.

The object of the present invention is, therefore, to provide a pharmaceutical composition which formulation ensures a chondroprotective, anti-inflammatory, and analgetic effect, an effective treatment of degenerative dystrophic diseases of extremity joints and intervertebral disks, a convenience of using the medicine, decrease in side effect risks, and to provide an alternative medicament.

The object set is achieved by development of the pharmaceutical composition for oral administration, comprising chondroitin sulfate salt and glycosamine sulfate salt, ibuprofen as a nonsteroidal anti-inflammatory drug, and auxiliary substances, characterized in that the ingredients are comprised in the following ingredient ratio (% w/w):

Chondroitin sulfate salt 20 to 30

Glucosamine sulfate salt 30 to 36

Ibuprofen 10 to 15 and auxiliary substances Q. S.

A preferred pharmaceutical composition for oral administration comprises chondroitin sulfate salt and glycosamine sulfate salt, ibuprofen as a NSAID, and auxiliary substances, wherein auxiliary substances comprise disintegrants, glidants, a capsule material, and colorants in the following ingredient ratio (% w/w):

Chondroitin sulfate salt 20 to 30

Glucosamine sulfate salt 30 to 36 lbuprofen 10 to 15

Glidants 1 to 3

Forming material 10 to 13

Colorants 0.01 to 0.03

Disintegrants Q. S.

Chondroitin sulfate is a substance that belongs to mucopolysaccharides. It is the main structural component of cartilaginous tissue. Besides, chondroitin sulfate takes part in the production of bone tissue, filaments as well as in the maintenance of vascular wall flexibility and elasticity. Chondroitin sulfate has one more interesting property, it participates in the formation of urinary colloids and prevents urinary salts from depositing which may become a substrate for formation calculi in the urinary tracts. Numerous studies have shown that chondroitin sulfate not only prevents a joint cartilage tissue from being eroded in osteoarthrosis and arthritis, but also assists in restoring it. Chondroitin sulfate improves mobility of extremity joints and vertebral column joints, reduces or removes joint soreness and crepitus. The efficacy of chondroitin sulfate has been proven not only clinically but also instrumentally: patients that received this substance had a significant improvement in X-ray indices. It has been found experimentally that the introduction of chondroitin sulfate salt into the composition in a quantity of between 20% and 30% of the total weight of composition makes it possible to ensure a chondroprotective effect of the medicine, to improve its efficacy, and to reduce a need for NSAIDs for patients, suffering from arthrosis of knee joints and arthrosis of other joints which in turn makes is possible to decrease side effect risks.

The role which glucosamine sulfate plays in the termination or reverse development of a joint degeneration process is most likely associated directly with its ability to act as the most important substrate for glycosaminoglycans and as a basis of hyaluronic acid as well as to stimulate the biosynthesis of the above substances which are required to form proteoglycans found in the joint structure matrix. A successful treatment of osteoarthritis must control pain effectively as well as slow down or ensure the reverse development of joint degeneration processes. Biochemical and pharmacological data reported in conjunction with the results of studies performed on laboratory animals as well as with the participation of human patients have shown that glucosamine sulfate is able to meet both these criteria. It has been found experimentally that the introduction of glucosamine sulfate salt in a quantity of between 30% and 36 % of the total weight of composition makes it possible to ensure a chondroprotective and anti-inflammatory effect of the medicine and prevents a destructive effect of glucocorticoids on chondrocytes and a deranged biosynthesis of glycosaminoglycans induced by NSAIDs from occurring thereby decreasing side effect risks.

lbuprofen is a nonsteroidal anti-inflammatory drug being a phenylpropionic acid derivative. It has anti-inflammatory, analgetic, and antipyretic effect. The efficacy of this medicine is caused by inhibition of prostaglandins synthesis via blocking cyclooxygenase (COX). lbuprofen suppresses platelet aggregation. If used for a long period of time, ibuprofen has a desensitizing effect. It has been found experimentally that the introduction of ibuprofen in a quantity of between 10% and 15% of the total weight of composition makes it possible to ensure an analgetic effect of the medicine, its high efficacy in reducing a pain syndrome in degenerative dystrophic diseases of extremity joints and intervertebral disks.

The use of the above mentioned ingredients in the pharmaceutical composition of the invention in said quantities ensures the increase in number of similar medicines for treatment of joint diseases.

Preferably, sodium chondroitin sulfate is used as chondroitin sulfate salt. Also preferably, a complex salt of glycosamine sulfate and potassium chloride is used as glycosamine sulfate salt.

Advantageously, the pharmaceutical composition comprises magnesium stearate and/or stearic acid as the glidants. The glidants may perform several functions, for example, may ensure gliding, perform a lubricating function while preventing adherence from occurring, and their activity can be displayed in different ways. They ensure accuracy and consistency of a medicine dosage, reduce tablet cleavage, scratches, and lamination of tablets Introduction of glidants in a quantity of between 1 % and 3% of the total weight of composition is the most optimum quantity that was found experimentally

Forming material in the sense of this invention are considered to be further excipients that assist in forming tablets or pellets or to be film-forming high-molecular substances capable of forming elastic films having a certain mechanical strength which are used to produce coatings of capsules. In this case, gelatin is preferably used as the capsule material. A quantity of gelatin of between 10% and 13% of the total weight of composition is the most optimum quantity that was found experimentally

The colorants are added to the capsule composition for the purpose of improving their appearance. In addition, they serve to identify the therapeutic group of drugs such as hypnotics, poisonous drugs (mercuric chloride) The pharmaceutical composition comprises titanium dioxide and/or a blue lacquer colorant as the colorant. A quantity of the colorants of between 0.01% to 0.03% of the total weight of composition is the most optimum quantity that was found experimentally.

It is expedient to use at least one of the substances selected from the group consisting of cornstarch, crospovidone, a pregelatinized starch, silicon dioxide, sodium starch glycolate, and microcrystalline cellulose as the disintegrants The disintegrants are introduced into the medicine in order to disintegrate quickly the capsule in a liquid medium (such as water or gastric juice) which is required for the release and subsequent absorption of the pharmaceutical substance

The composition may further comprise pharmacologically acceptable excipients Such excipients include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds , 2nd edition, Marcel Dekker, 2002). These can be referred to herein as "pharmaceutically acceptable excipients" to indicate they are combined with the active compounds and can be administered safely to a subject for therapeutic purposes.

The dosage form of the pharmaceutical composition may be a capsule, tablet, and pellet.

The pharmaceutical composition may be produced as follows:

The raw materials such as glucosamine sulfate salt, chondroitin sulfate salt, ibuprofen, and auxiliary substances are produced in accordance with the procedures established. At the same time, the samples of the raw materials are selected and analyzed using the conventional methods of analysis and validation of raw materials for the purpose of quality control. The active ingredients are then weighed in, accordance with the specifications. Afterwards, said raw materials are mixed with for example a 75 cu ft Patterson Kelley cross flow blender in accordance with the specifications. The Quality Assurance Department takes then samples of the resulting blend and the Quality Control Laboratory analyzes them to determine whether the blend complies with the specifications or not. The dosage form is made, for example, in the form of a capsule. Encapsulation is carried out using encapsulation machines, for example, lma Encapsulation Machines or Bosch Encapsulation Machines, in transparent/opaque capsules. Further, the Quality Control Department analyzes the finished products, and the finished products are then packed.

The efficacy of the pharmaceutical composition in accordance with the present invention was studied at the Locomotorium Clinical Physiology and Pathology Department, the Institute of Gerontology, the Academy of Medical Science of Ukraine. The pharmaceutical composition comprises 250 mg of glycosamine sulfate salt, 200 mg of chondroitin sulfate salt, and 100 mg of ibuprofen as the active ingredients. The clinical trial involved 16 patients (average age is 64.2±1.9 years) suffering from Grade Il and Grade III osteoarthrosis of the knee joints (according to the Kellgren-Lawrence classification). All the patients were suffering from knee-joint pain (at the time of initial examination, pain was 40 mm and more on the Visual Analogue Scale (VAS)). The patients were given two capsules of the medicine twice a day during the first month; during the second month, the patients were examined. The control group included 16 patients with the same diagnosis (average age is 63.9±1.7 years) who were given the medicine containing 500 mg of glycosamine hydrochloride and 400 mg of chondroitin sulfate. One capsule of the medicine was given twice a day for two months. Treatment efficacy was evaluated using McGiII Pain Questionnaire (MPQ), VAS, algofunctional Lequesne index, Womac scales (pain; stiffness; activity limitations, daily living), the EuroQol -5D to measure health- related quality of life.

In two weeks, the patients who were given the pharmaceutical composition in accordance with the present invention already had a significant reduction in the intensity of pain syndrome on the Womac pain scale (prior to treatment - 58.5 ± 5.5; in two weeks - 40.7 ± 5.9; t=2.38; p=0.037), reduction in the stiffness score (prior to treatment - 57.8 ± 6.5; in two weeks - 36.7 ± 6.3; t=2.65; p=0.022), improvement in the daily activity score (prior to treatment - 64,6 ± 4, 1 ; in two weeks - 44.0 ± 6.1; t=2.82; p=0.017). In a month, in the group of the patients who were given the pharmaceutical composition in accordance with the present invention, the evidence of pain in the knee-joints reduced on the VAS pain scale (prior to treatment - 55.0 ± 3.1; in a month - 44.2 ± 4.9; t=2.32; p=0.041), on the Womac pain scale (prior to treatment - 58.5 ± 5.5; in a month - 38.7 ± 5.7; t=2.45; p=0.032). Also, there were observed reduction in stiffness score on the Womac stiffness scale (prior to treatment - 57.8 ± 6.5; in a month - 37.5 ± 7.2; t=2.96; p=0.013) and improvement in daily activity score (prior to treatment - 64.6 ± 4.1; in a month - 42.1 ± 5.4; t=3.51 ; p=0.005). In a month following the termination of taking the medicine, in the patients who were given the said pharmaceutical composition, the intensity of pain remained smaller as compared with the scores prior to treatment on the VAS scale (prior to treatment - 55.0 ± 3.1 ; in a month - 39.0 ± 4.1 ; t=2.26; p=0.049), on the Womac pain scale (prior to treatment - 58.5 ± 5.5; in a month -41.1 ± 5.5; t=1.40; p=0.20). At the same time, the stiffness scores increased (in a month of treatment - 37.5 ± 7.2; in two months - 47.0 ± 6.6) and the daily activity score on the Womac scale worsened (in a month of treatment - 42.1 ± 5.4; in two months - 49.4 ± 5.3), these scores being, however, lower than prior to treatment (57.8 ± 6.5 and 64.6 ± 4.1 , respectively). In the group of the patients who were given the second medicine, the evidence of pain syndrome after two months of treatment reduced significantly on the VAS scale (prior to treatment - 50.9 ± 3.9 in two months - 42.7 ± 4.6; t=3.1 ; p=0.011 ), on the Womac pain scale (prior to treatment - 47.0 ± 5.3; in two months - 30.4 ± 6.5; t=2.89; p=0.016). Also, there was observed reduction in the stiffness score (prior to treatment - 47.4 ± 5.1 ; in two months - 35.9 ± 6.6; t=2.67; p=0.023) and improvement in the daily activity score (prior to treatment - 50.0 ± 6.1; in two months - 38.3 ± 6.3; t=2.25; p=0.048).

Thus, for patients, who suffer from osteoarthrosis of the knee-joints, the composition in accordance with the present invention promotes a quick reduction in the intensity of pain syndrome (in two weeks). In a month following the termination of taking the medicine, a beneficial effect remains: pain in the knee-joints is reliable smaller as compared with the scores prior to treatment; there are observed increase in the stiffness score and the worsening of the daily activity score these scores being, however, iower than prior to treatment. No side effect was observed during the administration of the medicine. A substantial senescence of the population causes increase in the number of patients with osteoarthrosis; a timely diagnostics, a well- directed treatment, and the use of modifying agents (compounds of glycosamine and chondroitin) will promote the prevention of invalidization, improvement in quality of life, and an active longevity.

The invention further comprises the use of the pharmaceutical composition according to the invention for the treatment of degenerative dystrophic diseases of extremity joints and intervertebral disks.

A further objective of the invention is to provide a method of treating and/or preventing degenerative dystrophic diseases of extremity joints and intervertebral disks, by orally administering a pharmaceutical composition according to the invention and as described above.

In an embodiment of the inventive method the pharmaceutical composition can be orally administered at least once a day, preferably twice or thrice a day, especially preferred twice a day.

The present invention provides a pharmaceutical composition, which composition ensures a chondroprotective, anti-inflammatory, and analgetic effect, an effective treatment of degenerative dystrophic diseases of extremity joints and intervertebral disks, a convenience of using the medicine, decrease in side effect risks, and the provides an alternative medicament.

Claims

1. A pharmaceutical composition for oral administration comprising chondroitin sulfate salt and glycosamine sulfate salt, ibuprofen as a nonsteroidal antiinflammatory drug, and auxiliary substances, characterized in that the ingredients are comprised in the following ingredient ratio (% w/w):

Chondroitin sulfate salt 20 to 30

Glucosamine sulfate salt 30 to 36

Ibuprofen 10 to 15 and auxiliary substances Q. S.

2. A pharmaceutical composition according to claim 1 comprising chondroitin sulfate sait and giycosamine sulfate salt, ibuprofen as a nonsteroidal antiinflammatory drug, and auxiliary substances, characterised in that said auxiliary substances comprise disintegrants, glidants, a capsule material, and colorants in the following ingredient ratio (% w/w):

Chondroitin sulfate salt 20 to 30

Glucosamine sulfate salt 30 to 36

Ibuprofen 10 to 15

Glidants 1 to 3

Forming material 10 to 13

Colorants 0.01 to 0.03

Disintegrants Q.S

3. The composition according to claims 1 or 2, characterised in that said chondroitin sulfate salt is sodium chondroitin sulfate.

4. The composition according to any of claims 1 to 3, characterised in that said glycosamine sulfate salt is a complex salt of glycosamine sulfate and potassium chloride.

5. The composition according to any of claims 2 to 4, characterised in that said disintegrants comprise at least one of the substances selected from the group consisting of cornstarch, crospovidone, a pregelatinized starch, silicon dioxide, sodium starch glycolate, and microcrystalline cellulose.

6. The composition according to any of claims 2 to 5, characterised in that said glidants comprise magnesium stearate and/or stearic acid.

7. The composition according to any of claims 2 to 6, characterised in that said forming material is a capsule material and comprises gelatin.

8. Process for preparing a pharmaceutical composition according to claims 1 to 7 by weighing and subsequent mixing of the raw materials.

9. Use of the pharmaceutical composition according to any of claims 1 to 7 for the treatment of degenerative dystrophic diseases of extremity joints and intervertebral disks.

10. Use according to claim 9 for the treatment of a pain syndrome during a pain exacerbation phase in primary osteoarthrosis and secondary osteoarthrosis.

11. Method of treating and/or preventing degenerative dystrophic diseases of extremity joints and intervertebral disks or a pain syndrome during a pain exacerbation phase in primary osteoarthrosis and secondary osteoarthrosis, by orally administering a pharmaceutical composition according to claims 1 to 7.