WO2010038239A2 - Pharmaceutical composition comprising coenzyme q10 - Google Patents

Pharmaceutical composition comprising coenzyme q10 Download PDF

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Publication number
WO2010038239A2
WO2010038239A2 PCT/IN2009/000525 IN2009000525W WO2010038239A2 WO 2010038239 A2 WO2010038239 A2 WO 2010038239A2 IN 2009000525 W IN2009000525 W IN 2009000525W WO 2010038239 A2 WO2010038239 A2 WO 2010038239A2
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pharmaceutical composition
periodontal
pockets
administration
adapted
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PCT/IN2009/000525
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French (fr)
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WO2010038239A3 (en
Inventor
Saumya Sharma
Srinath Thakur
Swati Setty
Rajesh Kulkarni
Shirishkumar Kulkarni
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Saumya Sharma
Srinath Thakur
Swati Setty
Rajesh Kulkarni
Shirishkumar Kulkarni
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Priority to IN2073MU2008 priority Critical
Priority to IN2073/MUM/2008 priority
Application filed by Saumya Sharma, Srinath Thakur, Swati Setty, Rajesh Kulkarni, Shirishkumar Kulkarni filed Critical Saumya Sharma
Publication of WO2010038239A2 publication Critical patent/WO2010038239A2/en
Publication of WO2010038239A3 publication Critical patent/WO2010038239A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35Ketones, e.g. benzophenone
    • A61K8/355Quinones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • A61K31/122Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0063Periodont
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Abstract

A pharmaceutical composition for administration in gum pockets caused by periodontal disease, consisting: coenzyme Q10 and pharmaceutically acceptable excipients selected from the group comprising solubilizer; biodegradable polymer; solvent, and/or combinations thereof. A process for making a pharmaceutical composition for administration in pockets in gums caused by periodontal disease, consisting: coenzyme Q10 and pharmaceutically acceptable excipients wherein the solubilizer was dissolved in the solvent with stirring to obtain a clear solution followed by addition of the biodegradable polymer to this solution with stirring to obtain a clear solution; to this solution CoQ10 was added with vortexing to form a uniform suspension.

Description

PHARMACEUTICAL COMPOSITION COMPRISING COENZYME QlO

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising CoQlO used in treating and preventing periodontal disease.

BACKGROUND OF THE INVENTION

Coenzyme QlO, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQio, CoQ, QlO, or Q, exists naturally in the mitochondria of all cells in the human body, and has indispensable functions in the bioenergetics of human tissues, including the gingiva. Prior art discloses that a deficiency of CoQlO occurs in the gingiva of patients with periodontal disease.

Periodontal disease begins with plaque bacteria in the mouth. As plaque bacteria digest food, the by-products given off by the bacteria irritate the gums. As a result, the gums often become red, tender, swollen and exhibit a tendency to bleed. If left untreated, the irritants produced by the plaque bacteria eventually destroy the tissue that attaches the gums to the teeth. This causes the gums to begin to pull away from the teeth. As the gums pull away from the teeth, pockets are created that harbor yet more bacteria. The pockets therefore become ever larger as the cycle repeats. Eventually, the amount of gum loss is so large that the tooth is lost.

Oxidative stress is found to increase in the pathogenesis of periodontal disease. Therapeutic approaches to the use of anti-oxidants and prospects for its clinical use have been disclosed in the prior art. One of the conventional methods for treatment and/or prophylaxis of periodontitis is Scaling and Root Planing (SRP), which is a non-surgical periodontal therapy used to remove or eliminate the etiologic agents which cause inflammation, thus helping to establish a periodontum that is free of disease. Many clinical trials with oral administration of CoQlO to patients with periodontal disease have been conducted. The results have shown that oral administration of CoQlO increases the concentration of CoQlO in the diseased gingiva and effectively suppresses advanced periodontal inflammation (Wilkinson et al., 1975, 1976; Shizukuishi et al., 1986; Folkers, 1992; McRee et al, 1993).

Thus, CoQl O applied topically into the periodontal pocket may improve periodontal inflammation. Topical application is a convenient method in the dental clinical setting.

US patent 5,990,194 discloses a thermoplastic system in which a copolymer is dissolved in a solvent to form a liquid solution. The placement of the solution allows the solvent to dissipate away from the polymer leaving the polymer to coagulate or solidify into a solid structure. The placement of the solution can be anywhere within the body such as a periodontal pockets. The patent however does not disclose the use of CoQlO or antioxidants to treat periodontal diseases.

US patent 5,908,613 discloses a composition for treating pocketing in gums caused by periodontal disease, comprising CoQlO being between 0.05% and 75% of said composition by weight; melaleuca alternifolia extract oil being between 0.02% and 33% of said composition by volume; and a vegetable oil based solution medium into which said CoQlO and said melaleuca alternifolia extract oil are mixed.

Hanioca et al. discloses topical pharmaceutical composition of CoQlO wherein CoQlO is dispersed in soyabean oil at a concentration of 85 mg/ml.

We have now formulated a composition comprising Coenzyme QlO for application into periodontal pockets. The formulation of the invention has the following advantages over preformed biodegradable implants and microparticles (i) ease of administration and (ii) less complicated fabrication and less stressful manufacturing conditions for sensitive drug molecules. This system for topical application of CoQlO improves periodontitis alone or in combination with traditional non-surgical periodontal therapy.

OBJECTS OF THE INVENTION The object of the present invention is to provide a pharmaceutical composition for administration in gum pockets caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients selected from the group comprising: a) solubilizer b) biodegradable polymer c) solvent, and/or combinations thereof.

Another object of the present invention is to provide a method of enhancing dental health of humans and animals by topically administering the formulation consisting of Coenzyme QlO v and pharmaceutically acceptable excipients.

The object if the present invention is also to provide a long term therapy for the prevention ' and treatment of pockets in gums caused by periodontal disease comprising administering the present pharmaceutical composition to the patient a in need.

Another object of the present invention is to provide a method of treating or preventing gum diseases and tooth decay of humans and animals by topically administering the formulation consisting of Coenzyme QlO and pharmaceutically acceptable excipients .

Another objective of the present invention is to compare the clinical efficiency of traditional methods to treat periodontal disease with CoQlO suspension therapy.

Further, the present invention aims at reducing oxidative stress in periodontal tissues after non-surgical periodontal therapy. Another object of the present invention is a method of increasing patient compliance for the prevention and treatment of pockets in guns caused by periodontal disease comprising: reducing the frequency of administration of the present pharmaceutical composition.

Yet another objective of the invention is to provide a pharmaceutical composition for administration in pockets in gums caused by periodontal disease, wherein the frequency of administration of the composition of the invention is once a month.]

Another object of the invention is to provide a process for making a pharmaceutical composition for administration in pockets in gums caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients wherein the solubilizer was dissolved in the solvent with stirred to obtain a clear solution followed by addition of the biodegradable polymer to this solution with stirring to obtain a clear solution; to this solution CoQlO was added with vortexing to form a uniform suspension.

Yet another object of the present invention is to formulate a pharmaceutical composition consisting coenzyme QlO and pharmaceutically acceptable excipients; wherein the release of drug is from about 25% to 45% on 1st day; from about 35% to 55% on 2nd day; from about 50% to 70% on 4th day; from about 60% to 80% on 8th day; and at least about 70% on 10th day.

SUMMARY OF THE INVENTION

The present invention relates to a composition for administration in pockets in gums caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients. The invention is topically administered to improve the dental health of the gums. The present invention reduces the oxidative stress in periodontal tissues after non-surgical periodontal therapy. Treatment with CoQlO suspension along with scaling and root planning therapy is significantly better than scaling and root planning therapy alone in treating periodontal pockets. Hence, CoQlO suspension can be used as an effective adjunct to routine scaling and root planning. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition for administration in pockets in gums caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients selected from the group comprising: a) solubilizer b) biodegradable polymer c) solvent, and/or combinations thereof.

This composition is used for injection or for site-specific drug delivery. It comprised of a biodegradable polymer dissolved in a biocompatible carrier. When the liquid polymer system is placed in the body using conventional needles and syringes, it solidifies upon contact with aqueous body fluids to form a solid implant. If a drug is incorporated into the polymer solution, it gets entrapped within the polymer matrix as it solidifies, and is slowly released as the polymer biodegrades.

The poly(DL-lactide), lactide/glycolide copolymers, and lactide/caprolactone copolymers are most often used because of their degradation characteristics and their approval by the FDA. The biodegradable polymers are used in a range from about 10% to about 35% by weight of the formulation. More preferably, the biodegradable polymers are used in an amount from about 20% to 25% by weight of the formulation.

The solvents employed in this system to dissolve the polymers range from the more hydrophilic solvents, such as N-methyl-2-pyrrolidone (NMP), polyethylene glycol, tetraglycol and glycol furol, to the more hydrophobic solvents, such as triacetin, ethyl acetate and benzyl benzoate. PLGA provides the advantages of being fully biodegradable and subsequent obviating the problems associated with permanent implants based on nonbiodegradable polymers. The solubilizers include non-ionic and ionic surfactants. The non-ionic surfactant is selected from the group consisting of alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; tocopherol polyethylene glycol succinates; sugar esters; sugar ethers; sucroglycerides; and mixtures thereof. The ionic surfactant is selected from the group consisting of alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fatty acid derivatives of amino acids, carnitines, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; 'Ihono- ,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides;" citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof. Preferably, the solubilizer is polyethylene glycol- 15-hydroxystearate.

Coenzyme QlO is present in an amount from about 0.05% to 75% by weight of the composition of the present invention.

The following example serves to illustrate the invention and not intended to be limiting. Example

Figure imgf000007_0001
Brief Manufacturing Procedure

NMP was slowly added to Polyethylene Glycol- 15-Hydroxystearate and mixed to obtain clear solution. To this solution PLGA was added and mixed for suitable time to get a clear solution. To this clear solution, CoQlO was added and mixed thoroughly and vortexed to get a uniform suspension.

In Vitro Study

CoQlO contents of the formulation were determined by HPLC. The eluent was detected by UV detector at 275nm. The results are summarized in the table 1.

Table 1 : Percentage of CoQl O released over a period of 10 days

Figure imgf000008_0001

In Vivo Study

An in vivo study was carried out wherein an adjunctive therapeutic modality and comparison was done with routine SRP procedure.

Patients with periodontitis, aged 18-65 years, participated in this study having periodontal pockets with a probing depth between 4-6 mm in at least three permanent teeth. Sixty sites were randomly assigned to CoQlO and to control groups. Informed consent was obtained from each subject prior to the study. The study was randomized controlled study and was assessed by clinical and biochemical parameters at baseline, 1 month, 3 months and 6 months.

The patients were randomly divided into four groups:

Group A: Healthy patients undergoing orthodontic extractions (n=15)

Group B: Periodontitis patients undergoing extractions for grade III mobile teeth without prior scaling and root planning treatment (SRP) (n=15) Group C (Control): Patients undergoing SRP alone (n=15)

Group D (Study): Patients undergoing SRP with application of CoQlO suspension (n=15) Periodontal assessments were performed using the probing pocket depth PPD, Relative attachment level (RAL), plaque index (PI), gingival inflammation (GI), and Superoxide Dismutase (SOD) estimation and Malondialdehyde (MDA) estimation. Periodontal probing depth and clinical attachment loss were measured using a UNC 15 probe to the nearest mm at baseline, 1 month, 3 and 6 months. The biochemical assessment was performed based on colorimetric change of solution provided in the examination kit.

Probing Pocket Depth (PPD) is the distance from base of pocket to gingival margin in mms. The PPD of the selected teeth was noted using UNC 15 probe to the nearest mm at baseline, 1 month, 3 and 6 months.

Relative attachment level (RAL) is the distance from mark on stent till base of the pocket in mms. The sites of the deepest pocket were selected for relative attachment level measurements and UN probe 15 was used to determine the same.

Plaque Index (PI) is an index of evaluating the status of oral hygiene by measuring dental plaque, which occurs in areas adjacent to the gingival margin. Quigley and Helm proposed a system for scoring dental plaque. This was modified by Turesky et al to more explicitly describe mild to moderate plaque deposits.

Figure imgf000010_0001

Scoring by the Turesky modification:

(1) All teeth assessed except third molars (maximum number 28)

(2) A staining solution is used to show plaque deposits (Quigley and Turesky used basic fuchsin, Gordon used erythrosine)

(3) Both the facial and lingual surfaces examined (maximum number 56)

(4) A score is assigned to each facial and lingual nonrestored surface

Total score = SUM (scores for all facial and lingual surfaces) Plaque Index = (total score) / (number of surfaces examined) Interpretation:

• A score of 0 or 1 is considered low.

• A score of 2 or more is considered high.

The Gingival Index (GI) was developed by Loe and Silness to describe the clinical severity of gingival inflammation as well as its location.

Figure imgf000010_0002
Teeth examined:

(1) maxillary right first molar

(2) maxillary right lateral incisor

(3) maxillary left first bicuspid (4) mandibular left first molar

(5) mandibular left lateral incisor

(6) mandibular right first bicuspid

Surfaces examined on each tooth: (1) buccal

(2) lingual

(3) mesial

(4) distal GI for a specific tooth = AVERAGE (points for the 4 surfaces).

GI for type of tooth (first molar, first bicuspid, lateral incisor) = AVERAGE (Gl for the 2 teeth)

GI for patient = AVERAGE (GI for all 6 teeth)

Figure imgf000011_0001
Superoxide dismutase (SOD) catalyzes the dismutation of super oxide into oxygen and hydrogen peroxide. It is an important antioxidant defense in nearly all cells exposed to oxygen. Superoxide is one of the main reactive oxygen species (ROS) in the cell and as such, SOD serves as a key antioxidant. Superoxide ion is involved in oxidation of pyrogallol at alkaline pH (8.5). The SOD inhibits oxidation of pyrogallol, which can be determined as an increase in absorbance at 420 nm. Buffers used:

Tris buffer, 0.05m (8.5 pH) containing ImM EDTA Pyrogallol, 2OmM Heparinized blood was centriftjged and plasma was removed, RBCs were washed with 0.9% NaCl. Distilled water was added to the RBCs and contents were mixed, centrifuged and clear hemolysate (H) was collected. Calculations: SOD units/ml of hemolysate = [(C - T) /C*50]*2000 SOD units/ ml serum = [(C - T)/C*50]*1000 1 unit of SOD is the enzyme required to cause 50% inhibition of pyrogallol antioxidation.

Malondiadehyde (MDA) is the end product of lipid peroxidation and it is a sensitive and convenient marker of lipid peroxidation. MDA is estimated as thiobarbituric acid reactive substance (TBARS). MDA reacts with thiobarbturic acid (TBA) at 1000C in acidic medium to form a pink colored complex. The color intensity of MDA-TBA complex is measured at

535nm by colorimetry. MDA concentration is calculated.

Reagents: MDA reagent Calculation:

MDA in mmoles/lOOml = (OD of sample * total reaction volume)/(nanomolar extinction coefficient*sample volume)

Data obtained after treatment was put to statistical analysis using statsitical package for social sciences (SPSS-version 1 1). Mean values of the observed variables were put to statistical tests like paired t-test and unpaired t test. For all statistical tests P values less than 0.05 were considered as significant. Results Results of PPD and RAL scores for both control and test groups showed significant improvements, but improvement in the study group was more significant than the control group as depicted in tables 2 and 3 respectively.

Analysis of PI and GI scores form specific sites depicted no statistical significance for PI scores among test and controls respectively (Table 4). However, in the test group a significant reduction in the GI was observed at the end of the 1st month indicating better healing of the tissues at test sites (Table 5).

A significant increase in the levels of SOD was observed for both control and test samples from baseline to the end of the study period respectively. However, SOD levels in the study samples increased markedly compared to that of control samples indicating the anti-oxidant activity of CoQlO (Table 6).

A significant decrease in the MDA levels was observed for both control and test samples from baseline to the end of the study period respectively. However, in the test sample a significant reduction in the MDA levels was observed when compared to control samples (Table 7). As the study progressed mild reduction in SOD levels and increase in MDA was observed in both groups, which was not statistically significant when compared to baseline scores.

Table 2: Comparison of different periods of treatment by PPD for specific sites between control and study groups. (n=15)

Figure imgf000013_0001
Table 3: Comparison of different periods of treatment by RAL for specific sites between control and study groups. (n= 15) **

Figure imgf000014_0001

PPD and RAL values increased for both groups mildly at the end of the 1st month till the end of the study period, which is not statistically significant when compared to the baseline values. This could be attributed to the single sitting of SRP for control group and single sitting of SRP and administration of CoQlO for the study group.

Table 4: Comparison of different periods of treatment by PI score for specific sites between control and study groups . (n=15)

Variable Group Mean SD t- value p-value

Baseline Control 3.20 0.41 -0.42 0.6789

Study 3.26 0.45

1 Month Control 2.33 0.48 0.38 0.7025

Study 2.26 0.45

3 Months Control 2.60 0.51 0.00 1.0000

Study 2.60 0.51

6 Months Control 2.66 0.49 0.00 1.0000

Study 2.66 0.49

Table 5: Comparison of different periods of treatment by GI score for specific sites between control and stud groups. (n=15)

Figure imgf000015_0001

The increase in the GI scores from the end of 1st month to the end of the study period could be attributed to the single application of 55mg CoQlO suspension in test sites.

Table 6: Comparison of different periods of treatment by SOD for specific sites between control and study groups. (n=15)

Figure imgf000015_0002
From the above results, we have surprisingly found that clinical efficiency of SRP with CoQlO suspension therapy is better than SRP alone in treating periodontal pockets and hence CoQlO suspension can be used as an adjunctive therapy to routine scaling and root planing. It was also found that oxidative stress increases in the periodontal tissues in the state of disease, and that it is markedly reduced in cases treated with CoQlO suspension compared to SRP treated sites. It has also been surprisingly found the formulation of the present invention reduces the frequency of administration preferably to about once a month thereby increasing the patient compliance. The present invention is used as long-term therapy for the treatment and prevention of pockets in gums caused by periodontal disease.

Claims

1. A pharmaceutical composition for administration in gum pockets caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients selected from the group comprising: a) solubilizer b) biodegradable polymer c) solvent, and/or combinations thereof.
2. The pharmaceutical composition in claim 1 wherein the solubilizer is selected from the group comprising ionic and nonionic solubilizers.
3. The pharmaceutical composition in claim 1 wherein the solubilizer has HLB value between 14 to 16 comprises polyethylene glycol-15-hydroxystearate.
4. The pharmaceutical composition in claim 1 wherein the biodegradable polymer is selected from the group comprising polyanhydrides, poly(ortho esters), phosphorus containing polymers, polyesters, poly-lactide-co-glycolide polymer.
5. The pharmaceutical composition in claim 1, wherein the composition comprises a biodegradable polymer in an amount from about 10% to about 35% by weight of the formulation.
6. The pharmaceutical composition in claim 1 wherein the solvent is selected from a group comprising N-methyl-2-pyrrolidone (NMP), polyethylene glycol, tetraglycol and glycol furol, to the more hydrophobic solvents, such as triacetin, ethyl acetate and benzyl benzoate.
7. The pharmaceutical composition in claim 1 forms in-situ gel.
8. The pharmaceutical composition of claim 1 includes in-situ gel forming suspension, implant, and depot.
9. The pharmaceutical composition of claim 1 adapted for enhancing dental health of humans and animals by topical administration.
10. The pharmaceutical composition of claim 1 adapted for treating or preventing gum diseases and tooth decay of humans and animals by topical administration.
11. The pharmaceutical composition of claim 1 adapted for long term therapy for the prevention and treatment of pockets in gums caused by periodontal disease.
12. The pharmaceutical composition of claim 1 adapted for use as adjunctive therapy with traditional non-surgical periodontal therapy.
13. The pharmaceutical composition of claim 1 adapted for use for reducing oxidative stress in periodontal tissues after non-surgical periodontal therapy.
14. The pharmaceutical composition of claim 1 adapted for increasing patient compliance for the prevention and treatment of pockets in guns caused by periodontal disease by reducing the frequency of its administration.
15. A pharmaceutical composition as in claim 1 wherein the formulation is administered once a month.
16. A process for making a pharmaceutical composition for administration in pockets in gums caused by periodontal disease, consisting: coenzyme QlO and pharmaceutically acceptable excipients wherein the solubilizer was dissolved in the solvent with stirring to obtain a clear solution followed by addition of the biodegradable polymer to this solution with stirring to obtain a clear solution; to this solution CoQlO was added with vortexing to form a uniform suspension.
17. A pharmaceutical composition as in claim 1 where the Coenzyme QlO is present in concentrations from about 0.05% to 75% by weight.
18. The pharmaceutical composition consisting: coenzyme QlO and pharmaceutically acceptable excipients; wherein the release of drug is from about 25% to 45% on 1st day; from about 35% to 55% on 2nd day; from about 50% to 70% on 4th day; from about 60% to 80% on 8th day; and at least about 70% on 10th day.
PCT/IN2009/000525 2008-09-26 2009-09-25 Pharmaceutical composition comprising coenzyme q10 WO2010038239A2 (en)

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IN2073MU2008 2008-09-26
IN2073/MUM/2008 2008-09-26

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5278201A (en) * 1988-10-03 1994-01-11 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US6200550B1 (en) * 1998-12-11 2001-03-13 Q-Pharma, Inc. Oral care compositions comprising coenzyme Q10

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5278201A (en) * 1988-10-03 1994-01-11 Atrix Laboratories, Inc. Biodegradable in-situ forming implants and methods of producing the same
US6200550B1 (en) * 1998-12-11 2001-03-13 Q-Pharma, Inc. Oral care compositions comprising coenzyme Q10

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WO2010038239A3 (en) 2010-06-24

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