WO2010150127A1

WO2010150127A1 - Glucosamine formulations

Info

Publication number: WO2010150127A1
Application number: PCT/IB2010/052607
Authority: WO
Inventors: Qizhi Zhang; Shuai Qian; Bernard Pak Li Chan; Benjamin Tak Kwong Lee
Original assignee: Jiwa Pharmaceuticals Limited
Priority date: 2009-06-25
Filing date: 2010-06-11
Publication date: 2010-12-29
Also published as: CN101926808A

Abstract

Glucosamine supplements are widely used for the treatment of osteoarthritis. However, glucosamine has poor and variable gastrointestinal absorption although it is usually taken orally. The current invention provides new formulations and/or methods that could increase the plasma concentration by 1.3 to 4 times after oral administration of glucosamine with an additional absorption enhancer. In the current invention, chitosans and cyclodextrins were identified as suitable absorption enhancers for glucosamine.

Description

Glucosamine Formulations

Field of the Invention

This invention relates to glucosamine formulations, particularly those including an absorption enhancer for enhancing glucosamine absorption in a mammal, more particularly those for achieving acceptable therapeutic effect of glucosamine with reduced number of oral administrations and/or reduced amount of dose per day.

Background of the Invention

Osteoarthritis, the most common disorder of the synovial joints in middle aged and elder people, is characterized predominantly by a focal or global loss of articular cartilage, bone changes and an imbalance in inflammatory and non-inflammatory pathways including proteolysis of aggrecans and collagens combined with distortion of their synthesis by chondrocytes. It is a source of disability, quality of life impairment and a considerable burden to any health care system. It is estimated that more than one third of people over 45 years have osteoarthritis-related symptoms.

Glucosamine (2-amino-2-deoxy-d-glucose), an amino monosaccharide, is a natural component found in connective tissues and gastrointestinal mucosal membranes. Glucosamine is shown to block NFK B activation in IL-I -stimulated human chondrocytes. It also appears to decrease matrix metalloproteinase expression in cultured chondrocytes and to increase the expression of a major cartilage proteoglycan. Glucosamine supplements are widely used for the treatment of osteoarthritis.

However, glucosamine has poor and variable gastrointestinal absorption although it is usually taken orally. In order to be therapeutically effective, the current recommended oral dose is 1500 mg per day. Accordingly, a patient is required to take current commercial product (such as Glucosamine Sulfate 550, made by General Nutrition Corp.) three times per day. However, it is reported that the patient compliance is as high as 87% when administered once a day as when compared to 39% for multiple administrations per day. If a single administration once a day is desired, the amount of glucosamine per serving is required to be as high as 2000 mg as in the commercially available Wellese™ glucosamine solution, which results in relatively large amount of solution (30ml) to be taken at once. Likewise, patients are seldom to take their entire daily oral glucosamine tablet dose at once (3-4 tablets and each tablet weight about lgm) due to the shear large size and amount. Therefore, there is a need to develop new formulations and/or methods with increased absorption of glucosamine through oral administration, which may at least reduce the dosing frequency and/or dosing amount per day of glucosamine with low amount of glucosamine per serving while maintaining the same therapeutic effect of glucosamine of the standard dose of marketed product.

Objects of the Invention

Therefore, it is an object of this invention to resolve at least one or more of the problems as set forth in the prior art. Particularly, it is an object of the current invention to provide formulations and/or methods for oral administration of glucosamine that could be administered with reduced or same amount of glucosamine per serving but with reduced number of administration per day while maintaining effectiveness. As a minimum, it is an object of this invention to provide the public with a useful choice.

Summary of the Invention

Accordingly, this invention provides an oral formulation including: - glucosamine; and an absorption enhancer for enhancing absorption of glucosamine in a mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

Preferably, the bioavailability of glucosamine in said mammal after administering the oral formulation of the current invention is 1.37 to 3.21 times, more preferably 2.18 to 3.21 times, and even more preferably 1.37 to 2.18 times, higher than after administering the oral formulation without said absorption enhancer.

Advantageously, the glucosamine is in a form of a pharmaceutically acceptable salt including hydrochloride, and sulfate of a metal selected from the group consisting of sodium, potassium, calcium, and magnesium.

Preferably, the adsorption enhancer is selected from the group consisting of chitosan, cyclodextrin, and their mixtures thereof.

More preferably, the absorption enhancer is chitosan, which is preferably selected from the group consisting of chitin derivatives, and oligomers and polymers of N-acetyl-glucosamine. In the case when the chitosan are oligomers and polymers of N-acetyl-glucosamine, the degree of deacetylation is preferred to be between 40 to 97%, more preferably between 60 to 96%, and even more preferably between 70 to 95%.

Optionally, the chitosan has a molecular weight of 3,000 to 1,000,000 Da, more preferably 3,800 to 750,000 Da, and even more preferably 3,800 to 500,000 Da.

Preferably, the chitosan is in the form of a salt selected from the group consisting of nitrate, phosphate, glutamate, lactate, citrate, hydrochloride, and acetate. The chitosan is additionally preferred to be in the form of a salt of hydrochloride or glutamate.

Alternatively, the absorption enhancer is cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, hydroxyproply-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and their mixtures thereof. More preferably, the cyclodextrin is selected from the group consisting of dimethyl-β-cyclodextrin, hydroxyproply-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and their mixtures thereof. Preferably, the oral formulation of the current invention is in the form of aqueous solution. In such cases, the glucosamine is preferred to be in a concentration of 20 to 250 mg/ml, more preferably 30 to 200 mg/ml, and even more preferably 40 to 150 mg/ml. When the absorption enhancer is chitosan, the chitosan is preferred to be in a concentration of 0.05% to 5% (w/v), more preferably 0.1% to 3.5% (w/v), and even more preferably 0.2% to 2% (w/v). When the absorption enhancer is cyclodextrin, the cyclodextrin is preferred to be in a concentration of 1% to 50% (w/v), more preferably 2% to 30% (w/v), and even more preferably 5% to 20% (w/v). The pH of the oral aqueous formulation of the current invention is preferred to be 1 to 8, more preferably 1.5 to 6, and even more preferably 1.5 to 5.

Alternatively, the oral formulation of the current invention is in the form of a solid preparation. In such cases, glucosamine is preferred to be in a content of 30% to 75%, and more preferably 45% to 70%, by weight of the solid preparation. The absorption enhancer is preferred to be chitosan, and the ratio by weight of glucosamine to chitosan is from 1 :0.007 to 1 :0.33, more preferably from 1 :0.017 to 1 :0.2.

Preferably, the mammal is rat or dog. Alternatively, the mammal is human. It is another aspect of the current invention to provide a method of manufacturing an oral formulation including the steps of mixing glucosamine with an absorption enhancer for enhancing absorption of glucosamine in a mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

It is yet another aspect of the current invention to provide a method of administering glucosamine to a mammal including the step of administering an oral formulation including glucosamine and an absorption enhancer for enhancing absorption of glucosamine in said mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

Brief description of the drawings

Preferred embodiments of the present invention will now be explained by way of example and with reference to the accompanying drawings in which: Figure 1 shows the mean plasma-concentration profiles of glucosamine solution formulation of the current invention (QD-GIu) and Wellesse™ solution versus time after oral administration to male rats;

Figure 2 shows the mean plasma-concentration profiles of glucosamine tablet formulation of the current invention (QD-GIu) and Voltaflex™ tablet versus time after oral administration to beagle dogs.

Detailed Description of the Preferred Embodiments

This invention is now described by way of example with reference to the figures in the following paragraphs. Objects, features, and aspects of the present invention are disclosed in or are apparent from the following description. It is to be understood by one of ordinary skilled in the art that the present discussion is a description of exemplary embodiments only, and is not intended as limiting the broader aspects of the present invention, which broader aspects are embodied in the exemplary constructions.

Glucosamine (molecule weight 179.17), 2-amino-2-deoxy-D-glucose, is an amino monosaccharide having the following chemical formula:

Glucosamine is highly soluble in water and has a pKa of 6.91. Glucosamine is an essential component of mucopolysaccharides and chitin. Glycosaminoglycans (mucopolysaccharides) are large complexes of negatively charged carbohydrate chains that are incorporated into mucous secretions, connective tissue, skin, tendons, ligaments, and cartilage. Glucosamine and its acetylated derivative, N-acetylglucosamine, are readily synthesized in the body from glucose.

Because of its high concentration in joint tissues, it is generally believed that glucosamine supplements would provide symptomatic relief for osteoarthritis. In vitro studies have shown that glucosamine stimulates the production of proteoglycans via chondrocyte activation and increases sulfate uptake by articular cartilage, thus helping to rebuild cartilage.

Glucosamine can be administered orally, intramuscularly (i.m.) or intravenously (i.v.). The recommended adult oral dose is typically 1500 mg per day for acceptable therapeutic effect. The absolute oral bioavailability of glucosamine has been estimated to be between 3% and 6% in horses, 12% in dogs, 19% in rats, and 26% in man. The low oral bioavailability is believed to be due to glucosamine poor gastrointestinal absorption according to Aghazadeh-Habashi et al. report (Aghazadeh-Habashi A, Sattari S, Pasutto FM. Single Dose Pharmacokinetics and Bioavailability of Glucosamine in the Rat. Journal of Pharmacy & Pharmaceutical Sciences. 2002, 5(2): 181-184; and Aghazadeh-Habashi A, Ibranhim A, Carran J. et al. Single Dose Pharmacokinetics and Bioavailability of Butyryl Glucosamine in the Rat. Journal of Pharmacy & Pharmaceutical Sciences. 2006, 9(3): 359-364).

According to the present invention, there is provided a formulation for oral administration to a mammal which includes glucosamine and an absorption enhancer. A particular advantage of the formulations of the current invention is that bioavailability of glucosamine is increased by 1.3 times to 4 times than existing commercial products without the absorption enhancer. In other words, this invention provides glucosamine oral formulations of the current invention that includes an absorption enhancer for enhancing absorption of glucosamine in a mammal such that the same amount of glucosamine can achieve higher bioavailability of glucosamine after oral administration. In the formulations of the current invention, other than the natural form, glucosamine may be present in a form of a pharmaceutically acceptable salt include, but not limited to, the hydrochloride, glutamate or sulfate of a metal selected from Na, K, Ca, Mg. The glucosamine in the pharmaceutical formulation may have an amount of 750 to 1500 mg per serving.

An absorption enhancer is added to the formulation of the current invention to enhance absorption of glucosamine in an animal, more preferably human. Suitable enhancers should be: 1) compatible with glucosamine physicochemically; 2) safe (for example, minimum local irritation and toxicity); 3) and ingestible, more preferably tasty. Generally, the absorption enhancer should be potent, pharmacologically inert at the concentration used (nontoxic and nonallergenic), and have no irritant or disruptive effect on the gastrointestinal mucosa. The absorption enhancer should be compatible with glucosamine or its salt and physically rather than covalently associated with glucosamine. The absorption enhancer should be able to remain in contact with the mucosa long enough to achieve good effect, and the effect should be transient and reversible. Besides, the absorption enhancer should have no taste or offensive odor, should preferably be readily available and inexpensive. Several classes of compounds are known to be able to enhance absorption of pharmaceutical compounds other than glucosamine, including fatty acids (for example oleic acid) and their derivatives (for example sodium caprate), chelators (for example EDTA and polyacrylates like carbomers), cellulose ethers, surfactant (for example Na-deoxycholate, Na-glycocholate, Sodium lauryl sulfate (SLS); Tween 80), chitosans, and cyclodextrins ([1] Hans E. Junginger. (2008) Chapter 6: Excipients as Absorption Enhancers. Biopharmaceutics Applications in Drug Development. Edited by Krishna, Rajesh; Yu, Lawrence. Springer publication. 139-174.). However, it cannot be predicted whether the above classes of compounds can fulfill the above requirements and thus can be used as absorption enhancer of glucosamine. In fact, during the development of the formulations of the current invention, unexpectedly, it was found that:

Fatty acids and chelators precipitate with glucosamine, and are therefore not suitable as absorption enhancer of glucosamine.

Experiments showed that cellulose ethers lead to lower absorption of glucosamine in animals than existing products. Surfactants have safety and taste issues and are therefore not suitable to be used as absorption enhancer of glucosamine due to regulatory approval and customer acceptance concerns.

Chitosans and cyclodextrins were identified as suitable glucosamine absorption enhancers in the current invention. Details of the use of these classes of compounds as glucosamine absorption enhancer will be discussed below.

Chitosan is a cationic biopolymer comprising glucosamine and N-acetyl glucosamine that has bio-adhesive properties The term "chitosan" includes all derivatives of chitin, or poly-N-acetyl-D-glucosamine, including all polyglucosamines and oligomers of glucosamine materials of different molecular weights, in which the greater proportion of the N-acetyl groups have been removed through hydrolysis (deacetylation). In accordance with the present invention, the degree of deacetylation should preferably be in the range 40-97%, more preferably in the range 60-96% and most preferably be in the range 70-95%.

The chitosan, chitosan derivative or salt used in the present invention should preferably have a molecular weight (MW) in the range 3,000 to 1,000,000 Da, more preferably in the range 3,800 to 750,000 Da and most preferably in the range 3,800 to 500,000Da. Chitosans of lower molecular weights are preferred as it was reported ([I]) that high MW chitosans have higher cytoxicity on Caco-2 cells.

Salts of chitosan are suitable for us in the present invention. Salts with various organic and inorganic acids are suitable. Such suitable salts include, but are not limited to the nitrate, phosphate, glutamate, lactate, citrate, hydrochloride and acetate salts. Preferred salts are the hydrochloric acid and glutamic acid salts.

Chitosan derivatives and their salts are also suitable for use in this invention. Suitable chitosan derivatives include, but are not limited to, esters, ethers or other derivatives formed by bonding acyl and/or alkyl groups with the hydroxyl groups, but not the amino groups of chitosan. Examples include O-alkyl ethers of chitosan and O-acyl estrs of chitosan. Modified chitosans, such as those conjugated to polyethylene glycol may be used in the present invention. Conjugates of chitosan and polyethylene glycol are described in WO99/01498, which are also suitable to be used in the current invention. The cyclodextrins (CD) may be one or more of α-, β-, γ-CD, dimethyl-β-CD, randomly methylated-β-CD, hydroxypropyl-β-CD, and sulfobutylether-β-CD.

The pharmaceutical formulation of the current invention may be in any form suitable for oral administration including liquid and solid forms. In one aspect, the present invention provides a solution, preferably aqueous solution, for oral delivery including glucosamine or its pharmaceutically acceptable salt in a concentration of from 20 to 250 mg/ml (expressed as free base), more preferably from 30 to 200 mg/ml and most preferably from 40 to 150 mg/ml.

If the solutions of the current invention include chitosan as absorption enhancer, the concentration of chitosan is preferably from 0.05% to 5% (w/v), more preferably from 0.1% to 3.5% (w/v) and most preferably from 0.2 to 2% (w/v).

If the solutions of the invention include cyclodextrin as absorption enhancer, the concentration of cyclodextrin is preferably from 1% to 50% (w/v), more preferably from 2% to 30% (w/v) and most preferably from 5% to 20% (w/v). The aqueous solutions of the invention preferably have a pH of from 1 to 8, more preferably from 1.5 to 6 and most preferably from 1.5 to 5. The pH of the solutions may be adjusted to the desired value using any suitable organic or inorganic acid or organic or inorganic base. It was found that glucosamine precipitates from the solutions at pH higher than 8.

The aqueous solutions of the current invention may also contain other pharmaceutically acceptable ingredients well known in the art. Such ingredients included, but are not limited to preservatives (such as sodium benzoate, benzoic acid, potassium sorbate, parabens, phenylethyl alcohol or benzalkonium chloride), sweetening agents (for example sugar, sucrose, sorbitol, xylitol, erythritol, tagatose, sucralose, saccharin sodium, sodium cyclamate, aspartame, glycyrrhizin, and stevioside), flavours (such as peppermint, cherry, strawberry, orange juice) and other agents generally used in pharmaceutical liquid preparations.

In another general aspect, the present invention also provides a solid form of glucosamine which includes, but not limited to, tablet, capsule and granules. The solid preparations of the present invention preferably have a glucosamine or its pharmaceutically salts in an amount of from 30% to 75% by weight, more preferably 45% to 70% by weight.

If the solid preparations of the present invention comprise chitosan, its salts or derivatives thereof as the absorption enhancer, the ratio by weight of glucosamine hydrochloride to chitosan is preferably from 1 :0.007 to 1 :0.33, more preferably from 1 : 0.017 to 1 : 0.2.

It was found that a relatively high amount of cyclodextrin is required to enhance absorption of glucosamine in animal. When solid preparations containing cyclodextrins as absorption enhancer are prepared, the resulting preparations become difficult to be swallowed due to size. Therefore, solid preparations with cyclodextrins as the glucosamine absorption enhancer are not preferred.

The solid preparations of the present invention may also include other ingredients such as, but not limited to, fillers and diluents, binders, disintegrants, lubricants, sweetening agents and other agents generally used in pharmaceutical solid preparations. Fillers and diluents include microcrystalline cellulose, lactose, pregelatinized starch, mannitol and other suitable, known fillers and diluents, and mixtures thereof. Binders include polyvinyl pyrrolidone (PVP), hydroxypropyl methyl cellulose and other suitable, known binders. Disintegrants include cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium, sodium starch glycolate and other suitable, known disintegrants. Lubricants include talc, silicon dioxide, magnesium stearate, sodium stearyl fumarate, polyethyl glycols, sodium lauryl sulphate and other suitable, known lubricants and mixtures thereof. Suitable sweetening agents are described above.

The present invention also provides processes for preparing the compositions of the invention. The process for preparing the solutions of the invention comprises mixing the components in a suitable solvent such as water. The solid dosage form may be prepared using methods well known to those skilled in the art.

The following examples are provided to illustrate various implementations of the current invention without being limiting. Example 1 - Oral solutions of glucosamine with chitosans as absorption

enhancers

Glucosamine oral solutions with chitosans as absorption enhancers are prepared

according to Table 1 below and packaged in conventional oral liquid bottle or plastic

bag.

FORMULATION 1

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000 Chitosan 20 - 200

Saccharin sodium 100 Sodium benzoate 20 Beet red 0.5

Peppermint flavor 0.015 Water High Grade 7679 - 8359

FORMULATION 2

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000 Chitosan-HCl 20 - 200 Sucralose 100 Sodium benzoate 20 Beet red 0.5 Cherry flavor 0.015 Water High Grade 7679 - 8359

FORMULATION 3

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000 Chitosan glutamate 25 - 150 Sodium cyclamate 200 Benzoic acid 30 Amaranth 0.5 Orange flavor 0.015 Water High Grade 7619 - 8244

FORMULATION 4

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000

N-trimethyl chitosan chloride 25 - 150

Sucrose 500

Sucralose 50

Phenylethyl alcohol 20

Amaranth 0.5

Strawberry flavor 0.015

Water High Grade 7279 - 7904

Table 1 - Examples of formulations of oral solutions containing glucosamine and chitosans as absorption enhancer

Example 2 - Pharmacokinetic performance of formulations including chitosans

as glucosamine absorption enhancer on rats and beagle dogs

The bioavailability of the Formulation 2 of Example 1 (QD-GIu solution) was

compared to commercially available solution (Wellesse TM glucosamine-HCl 2000mg

/30ml) on rats and beagle dogs.

Rat test: Eight Sprague-Dawley male rats each weight 225 to 250 grams, were

administered orally by gastric perfusion at a dose of 360 mg/kg of body weight of test

(QD-GIu solution) or reference formulation (Wellesse TM solution), respectively.

Blood samples were drawn at selected times following each treatment. Blood levels of glucosamine for both the test and the reference drugs were determined and shown in Figure 1.

Rats administered with glucosamine formulation of the current invention showed higher bioavailabilitys than which given with Wellesse™ solution at all of the same time point.

Beagle dogs test: The bioavailability study was performed on 4 healthy Beagle dogs, with a mean age of 11.3 ± 0.5 months (range 11-12 months), mean weight of 13.0 ± 0.5 kg (range 12.5-13.7 kg). It was conducted as a single dose (1500 mg), open, randomized, crossover study, under fed conditions. Blood samples were drawn at selected times following each treatment. Plasma samples were analyzed using the HPLC method and the main pharmacokinetic parameters of glucosamine and the AUC (area under the plasma concentration-time curve) were summarized in Table 2 below. Wellesse™ solution QD-GIu solution

(reference) (current invention) t_max (h) 1.3 + 0.4 1.5 + 0.4

C_max (μg/ml) 9.27 ± 3.10 25.05 + 11.72

AUCiast (μg.h/ml) 15.50 + 8.06 48.68 + 27.00^*

AUCtot (μg-h/ml) 15.68 + 8.04 49.07 + 26.93^*

^*: significant difference (p<0.05) Relative bioavailability, F (%) = 3.21

Table 2 - Mean values of the main pharmacokinetic parameters of glucosamine

Based on literature reviews ([1], see page 156 - 165), it is believed that the

above data can be extrapolated to other similar salts of chitosan. Therefore,

formulations of the current invention containing chitosan as an absorption enhancer

resulted in 3.21 fold increased absorption of glucosamine in beagle dog as compared

to the commercial reference solution (without the absorption enhancer), indicating

that the formulations of the current invention has a potency of better therapeutic

effects than existing commercial products.

Example 3 - Oral solutions of glucosamine with cyclodextrins as absorption

enhancers Glucosamine oral solution with cyclodextrin as absorption enhancers are

prepared according to Table 3 below and packaged in conventional oral liquid bottle

or plastic bag.

FORMULATION 5

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000 Hydroxyproply-β-CD 1000 Sodium cyclamate 200 Butylparaben 20 Lemon yellow 0.5 Mango flavor 0.015 Water High Grade 6779 - 7279

FORMULATION 6

Ingredients Concentration (mg/10ml)

GlucosamineΗCl 1500 - 2000 Dimethyl-β-CD 1000 Aspartame 100 Methylparaben 10 Ethylparaben 10 Coccinellin 0.5 Berry flavor 0.015 Water High Grade 7379 - 7879 FORMULATION 7

Ingredients Concentration (mg/10ml)

Glucosamine-HCl 1500 - 2000

Sulfobutylether-β-CD 1000

Aspartame 100

Ethylparaben 10

Propylparaben 10

Erythrosine 0.5

Cherry flavor 0.015

Water High Grade 6779 - 7279

Table 3 - Examples of formulations of oral solutions containing glucosamine and cyclodextrins as absorption enhancer

Hydroxypropyl-β-CD, dimethyl-β-CD and sulfobutylether-β-CD were accurately

weighted and dissolved in water, respectively. Add glucosamine hydrochloride,

preservatives, sweetening agent and flavor, vortex a certain time until obtaining a

clear solution.

Example 4 - Pharmacokinetic performance of formulations including

cyclodextrins as glucosamine absorption enhancer on rats

The resulting formulations in Example 3 were compared with reference

commercial solution (Wellesse™) in a bioavailability study on rats, and the AUC

(area under the plasma concentration-time curve) were shown in Table 4 below. The column "T/R" represents the ratio by AUC of test formulation to reference

formulation.

Formulation AUCo-6h (μg.h/ml) T/R

Formulation 5 (hydroxypropyl-β-CD) 16.73 ± 15.97 218.1%

Formulation 6 (dimethyl-β-CD) 16.16 ± 16.45 210.7

Formulation 7 (sulfobutylether-β-CD) 10.55 ± 2.04 137.5%

Wellesse™ solution (reference) 7.67 ± 7.11 -

Table 4 - Relative bioavailability (Fr) after oral administration of different formulations containing 65mg glucosamine-HCl to rats

Example 5 - Oral tablets of glucosamine with chitosan as absorption enhancers

Glucosamine tablets with chitosan as absorption enhancer is prepared according

to Table 5 below.

FORMULATION 8

Ingredients mg/tablet

Glucosamine-HCl 250 - 750

Chitosan-HCl 10 - 200

Microcrystalline cellulose 90 - 200

Lactose 30 - 60

Cross-linked carboxymethyl cellulose sodium 0.5

Polyvinyl pyrrolidone K-30 Q . S .

Talc 5 - 22

Magnesium stearate 2.25 - 11

Total weight 450 - 1100

Table 5 - Examples of tablets containing glucosamine and chitosan as absorption enhancer Glucosamine hydrochloride, chitosan-HCl, microcrystalline cellulose, cross-linked carboxymethyl cellulose sodium and lactose were sieved through a Chinese Standard Sieve 60 mesh sieve, blended together, and granulated with polyvinyl pyrrolidone K-30 solution. The resulting granules were dried in a fluid bed drier at 60°C for 2 hours.The dried granules were sifted through a 20 mesh sieve. The granules obtained were lubricated with the remaining ingredients and compressed to form tablets.

Example 6 - Pharmacokinetic performance of glucosamine tablets on beagle dogs

The bioavailability of glucosamine tablets of Example 5 was compared to reference commercially available tablets (Novartis Corp., Voltaflex™ Filmtab 750 mg). The bioavailability study was performed on six healthy Beagle dogs. It was conducted as a single dose (1500 mg), open, randomized, crossover study, under fed conditions. Blood samples were drawn at selected times following each treatment. Blood

levels of the drug for both the test and the reference drugs were determined and

illustrated in Figure 2. According to the statistical analysis and as shown in Figure 2,

glucosamine plasma concentrations in the first two hour after oral administration of

the tablets of the current invention (QD-GIu tablets) were significantly higher than

those obtained after oral administration of the reference tablets (Voltaflex™). The

bioavailability of the tablets of the current invention is about 2 times of that of the

reference tablets in beagle dogs.

Example 7 - Oral capsules of glucosamine with chitosan as absorption enhancers

Glucosamine capsules with chitosan as absorption enhancer is prepared

according to Table 6 below.

FORMULATION 9

Ingredients mg/tablet

GlucosamineΗCl 250 - 750

Chitosan glutamate 10 - 200

Microcrystalline cellulose 45 - 110

Starch 1500 45 - 110

Cross-linked polyvinylpyrrolidone 9 - 55

SiO₂ 5 - 22

Magnesium stearate 2.25 - 11

Total weight 450 - 1100

Table 6 - Examples of capsules containing glucosamine and chitosan as absorption enhancer Glucosamine hydrochloride, chitosan glutamate, microcrystalline cellulose,

starch

1500, cross-linked polyvinylpyrrolidone, SiO₂ and magnesium stearate were sieved

through a Chinese Standard Sieve 60 mesh sieve, blended together, and filled into

empty capsule.

Example 8 - Oral granules of glucosamine with chitosan as absorption enhancers

Glucosamine granules with chitosan as absorption enhancer is prepared

according to Table 7 below.

FORMULATION 10

Ingredients mg/tablet

Glucosamine-HCl 250 - 750

Chitosan glutamate 20 - 200

Mannitol 600 - 1000

Lactose 600 - 1200

Hydroxypropyl methyl cellulose (lOOcps) Q. S.

Sodium stearyl fumarate 20 - 30

Total weight 2000 - 3000

Table 7 - Examples of granules containing glucosamine and chitosan as absorption enhancer Glucosamine hydrochloride, chitosan glutamate, mannitol and lactose were sieved through a Chinese Standard Sieve 60 mesh sieve, blended together, and granulated with hydroxypropyl methyl cellulose solution. The resulting granules were dried in a fluid bed drier at 60°C for 2 hours. The dried granules were sifted through a 20 mesh sieve. The granules obtained were lubricated with sodium stearyl fumarate and filled into the bag.

As shown in the above examples, the oral formulations of the current invention having glucosamine and an absorption enhancer for enhancing absorption of glucosamine can increase the bioavailability of glucosamine after oral administration when compared with existing products without the absorption enhancer by about 1.3 to 4 times. The oral formulations would therefore enhance the overall absorption of glucosamine in mammal through oral administration, and/or if desired, reduce the number of oral administrations per day of glucosamine.

While the preferred embodiment of the present invention has been described in detail by the examples, it is apparent that modifications and adaptations of the present invention will occur to those skilled in the art. Furthermore, the embodiments of the present invention shall not be interpreted to be restricted by the examples or figures only. It is to be expressly understood, however, that such modifications and adaptations are within the scope of the present invention, as set forth in the following claims. For instance, features illustrated or described as part of one embodiment can be used on another embodiment to yield a still further embodiment. Thus, it is intended that the present invention cover such modifications and variations as come within the scope of the claims and their equivalents.

Claims

CLAIMS:

1. An oral formulation including: glucosamine; and an absorption enhancer for enhancing absorption of glucosamine in a mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

2. The oral formulation of claim 1, wherein the bioavailability of glucosamine in said mammal after administering said oral formulation is 1.37 to 3.21 times higher than after administering the oral formulation without said absorption enhancer.

3. The oral formulation of claim 2, wherein the bioavailability of glucosamine in said mammal after administering said oral formulation is 2.18 to 3.21 times higher than after administering the oral formulation without said absorption enhancer.

4. The oral formulation of claim 2, wherein the bioavailability of glucosamine in said mammal after administering said oral formulation is 1.37 to 2.18 times higher than after administering the oral formulation without said absorption enhancer.

5. The oral formulation of any one of claims 1 to 4, wherein the glucosamine is in a form of a pharmaceutically acceptable salt including hydrochloride, and sulfate of a metal selected from a group consisting of sodium, potassium, calcium, and magnesium.

6. The oral formulation of any one of claims 1 to 5, wherein said absorption enhancer is selected from a group consisting of chitosan, cyclodextrin, and a mixture thereof.

7. The oral formulation of claim 6, wherein the absorption enhancer is chitosan.

8. The oral formulation of claim 7, wherein said chitosan is selected from a group consisting of chitin derivatives, oligomers, and polymers of N-acetyl-glucosamine.

9. The oral formulation of claim 8 wherein said oligomers and polymers of N-acetyl-glucosamine has a degree of deacetylation between 40 to 97%.

10. The oral formulation of claim 9 wherein said oligomers and polymers of N-acetyl-glucosamine has a degree of deacetylation between 60 to 96%.

11. The oral formulation of claim 10, wherein said oligomers and polymers of

N-acetyl-glucosamine has a degree of deacetylation between 70 to 95%.

12. The oral formulation of any one of claims 7 to 11, wherein the chitosan has a molecular weight of 3,000 to 1,000,000 Da.

13. The oral formulation of claim 12, wherein the chitosan has a molecular weight of 3,800 to 750,000 Da.

14. The oral formulation of claim 13, wherein the chitosan has a molecular weight of 3,800 to 500,000 Da.

15. The oral formulation of any one of claims 7 to 14, wherein the chitosan is in the form of a salt selected from a group consisting of nitrate, phosphate, glutamate, lactate, citrate, hydrochloride, and acetate.

16. The oral formulation of claim 15, wherein the chitosan is in the form of a salt of hydrochloride or glutamate.

17. The oral formulation of claim 6, wherein the absorption enhancer is cyclodextrin selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, dimethyl- β-cyclodextrin, randomly methylated- β-cyclodextrin, hydroxyproply-β-cyclodextrin, sulfobutylether- β-cyclodextrin, and a mixture thereof.

18. The oral formulation of claim 17, wherein the cyclodextrin is selected from a group consisting of dimethyl-β-cyclodextrin, hydroxyproply-β-cyclodextrin, sulfobutylether- β-cyclodextrin, and a mixture thereof.

19. The oral formulation of any one of claims 1 to 18 in the form of aqueous solution.

20. The oral formulation of claim 19, wherein the glucosamine is in a concentration of 20 to 250 mg/ml.

21. The oral formulation of claim 20, wherein the glucosamine is in a concentration of 30 to 200 mg/ml.

22. The oral formulation of claim 21, wherein the glucosamine is in a concentration of

40 to 150 mg/ml.

23. The oral formulation of any one of claims 19 to 22, wherein the absorption enhancer is chitosan in a concentration of 0.05% to 5% (w/v).

24. The oral formulation of claim 23, wherein the chitosan is in a concentration of 0.1% to 3.5% (w/v).

25. The oral formulation of claim 24, wherein the chitosan is in a concentration of 0.2% to 2% (w/v).

26. The oral formulation of any one of claims 19 to 22, wherein the absorption enhancer is cyclodextrin in a concentration of 1% to 50% (w/v).

27. The oral formulation of claim 26, wherein the cyclodextrin is in a concentration of

2% to 30% (w/v).

28. The oral formulation of claim 27, wherein the cyclodextrin is in a concentration of

5% to 20% (w/v).

29. The oral formulation of any one of claims 19 to 28 having a pH of 1 to 8.

30. The oral formulation of claim 29 having a pH of 1.5 to 6.

31. The oral formulation of claim 30 having a pH of 1.5 to 5.

32. The oral formulation of any one of claims 1 to 16 in the form of a solid preparation.

33. The oral formulation of claim 32, wherein the glucosamine is in a content of 30% to 75% by weight of the solid preparation.

34. The oral formulation of claim 33, wherein the glucosamine is in a content of 45% to 70% by weight of the solid preparation.

35. The oral formulation of any one of claims 32 to 34, wherein the absorption enhancer is chitosan, and the ratio by weight of glucosamine to chitosan is from 1:0.007 to 1:0.33.

36. The oral formulation of claim 35, wherein the ratio by weight of glucosamine to chitosan is from 1:0.017 to 1:0.2.

37. The oral formulation of any one of claims 1 to 36, wherein said mammal is rat or dog.

38. The oral formulation of any one of claims 1 to 36, wherein said mammal is human.

39. A method of manufacturing an oral formulation including the steps of mixing glucosamine with an absorption enhancer for enhancing absorption of glucosamine in a mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

40. A method of administering glucosamine to a mammal including the step of administering an oral formulation including glucosamine and an absorption enhancer for enhancing absorption of glucosamine in said mammal such that bioavailability of glucosamine in said mammal after administering said oral formulation is 1.3 to 4 times higher than after administering an oral formulation without said absorption enhancer.

41. An oral glucosamine formulation, including: glucosamine; and an absorption enhancer for enhancing absorption of glucosamine in a mammal, said absorption enhancer being selected from a group consisting of chitosan, cyclodextrin, and a mixture thereof.

42. A glucosamine oral formulation according to claim 41, wherein the formulation is adapted for daily administration to provide symptomatic relief for osteoarthritis.