FIELD OF THE INVENTION
The invention relates to the formulation of granules containing lactulose, isphagula husk and microcrystalline cellulose. Present invention further relates to the process of granulation which provides a stable formulation which assist in uniform dosing of the drug for the treatment of constipation in man.
BACKGROUND OF THE INVENTION
Lactulose or 4-O-.beta.-D-galactopyranosyl-D-glucose is a synthetic sugar used in the treatment of constipation. Isphagula husk or Psyllium is the common name used for several members of the plant genus Plantago whose seeds are used commercially for the production of drug to treat constipation.
The combination of lactulose and dietary fibers with good laxative effect is well known state of the art , US 4605646 describes synergistic formulation of dietary fibers with Lactulose the formulated composition has added advantages as the Lactulose masks the unacceptable taste of the fibers, and combination of both in suitable ratio provide a good laxative effect. The invention does not specifically describe the combination of isphagula and lactulose or their formulation.
US 4931554 describe solid composition of Lactulose with fibers formulated by incorporating Lactulose syrup onto moisture absorbing fiber product (which includes vegetable/ dietary fibers). However the invention does not specifically describe the combination of isphagula and lactulose or their formulation.
Lactulose and Isphagula combination are known to have good synergistic effect when used in combination. US 20080261916 describe the synergistic combination of prebiotic selected from Lactulose and plant extract which include psyllium (isphagula). The invention does not provide any teaching related to specific technique of formulation to address the shortcomings of available dosage forms.
The commercialized formulation is susceptible to physical separation during transportation and storage conditions. Suitable marketed formulation of lactulose and isphagula husk is available in the form of powder or granules. In powder formulation lactulose and isphagula are grinded and
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mixed uniformly. In granules formulation lactulose is in the form of granules and are blended with isphagula husk powder. Since both of the above formulation types involves the separate mixture of lactulose and isphagula components, the difference in their molecular density of leads to physical separation during the vigorous shipment process which in turn can lead to un-uniformity in dosage.
Hence there exist needs to provide a formulation which is uniform and is not susceptible to physical separation during the transportation. The present invention addresses the need by providing a granulation technique for the preparation of lactulose and isphagula granules in combination with microcrystalline cellulose and other excipients.
The aim of the present invention is to formulate granules so as to provide uniformity in dosing and to provide a more biologically efficient and cost effective formulation.
SUMMARY OF THE INVENTION
The present invention relates to the process of preparation of granules of lactulose, isphagula husk. More specifically the present invention relates to the process of preparation of granules of lactulose, isphagula husk and microcrystalline cellulose. Microcrystalline cellulose at high concentration serves as laxative so, the physiological efficacy of the final composition is enhanced due to the use of microcrystalline cellulose.
The formulation process involves the use of homogenous solution of lactulose optionally in combination with suspending agents or adsorbents in order to prepare granules. The granules are formulated using the wet granulation technique established in the art. Lactulose being a cellulose derivative serves as the role of binder. Lactulose is optionally used in combination with colloidal silicon dioxide also which helps in increasing the viscosity of the binder solution. The granules are formulated using excipients which includes sweetener, preservatives, adsorbent and suspending agents, stabilizers, flavor enhancers, antioxidants and acidifying agent. The swelling index of the final composition is around 16-17.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the process of preparation of granules of lactulose and isphagula husk.
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More specifically the present invention relates to the process of preparation of granules of lactulose, isphagula husk and microcrystalline cellulose.
The present invention further relates to the process of the preparation of granules using lactulose solution or lactulose with colloidal silicon dioxide as a binder solution which is added to the uniform blend of isphagula husk, microcrystalline cellulose with other excipients. The other excipients includes, but are not limited to sweetener, preservatives, adsorbent and suspending agents, stabilizers, flavor enhancers, antioxidants and acidifying agent
In another aspect of the invention the formulation involves the use of microcrystalline cellulose as diluent in the composition. The literature indicates that at high concentration it acts as laxative as it is cellulose derivates and retains water in the intestine. Hence addition of microcrystalline cellulose provides added advantage to the formulation by enhancing the biological efficacy of the final composition. Further Lactulose being a cellulose derivative serve as a dual role of both binder and active ingredient which reduces the additional requirement of binder in the formulation mixture. This in turn provides cost effectiveness and help in reducing the final bulk volume of the formulation. Use of colloidal silicon dioxide with lactulose solution as a binder solution enhances the viscosity of the final binder solution which aids in the process of granulation and helps in formulating the granules of uniform size.
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art.
The granules formulated as per the invention are formulated using active ingredients, diluents, binders, adsorbent or suspending agent, sweetners, flavoring agents, preservatives, colorants, stabilizers, antioxidants, flavor enhancers , acidifying agent and other pharmaceutically acceptable excipients.
Active ingredients includes lactulose and isphagula husk.
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Diluents are added to provide bulk to the formulation, suitable diluents includes, but are not limited to compound selected from the group consisting of microcrystalline cellulose, lactose, starch, sucrose, polysaccharides, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, and dextrins and mixtures thereof.
Binders are used to help hold the granules together and give it strength. Suitable binders include, but are not limited to methyl cellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxymethyl propylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, starch and the like and mixtures thereof. In the present invention lactulose, cellulose derivative serves as the role of binder.
Adsorbent or suspending agents are used for proving a uniform dispersion of weekly soluble compounds. Adsorbent or suspending agents are selected from the group consisting of colloidal silicon dioxide, natural or synthetic gums, resins, methylcellulose, and sodium carboxymethylcellulose.
Sweetners are used to mask the taste of bad-tasting active ingredients and making the formulation more patients compliant. Suitable sweeteners include, but are not limited to compound selected from the group consisting of aspartame, saccharin, sucralose, neotame, and acesulfame potassium.
Flavoring agents are used to mask the taste of bad-tasting active ingredients and making the formulation more patients compliant. Flavoring agents includes, but are not limited to compound selected from the group consisting of Lemon flavor, orange flavor, pineapple flavor, strawberry flavor, raspberry flavor, mixed fruit flavor.
Preservatives are used to protect the formulation from degradation during the storage conditions due to influence of microorganisms. Suitable preservatives includes, but are not limited to compound selected from the group consisting of sodium benzoate, methyl and propyl parabens.
Colorants are used to mask the un-uniform color of the final composition and to so that it is more patient compliant. Suitable colorant include, but are not limited to compound selected from the
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group consisting of Tartrazine, quinoline yellow, sunset yellow, Ponceau 4R, erythrosine and carmoisine.
Stabilizers are used to prevent the chemical degradation of the formulation during the storage conditions. Suitable stabilizers includes, but are not limited to compound selected from EDTA sodium and citric acid.
Antioxidants are used to prevent the formulation from chemical degradation as they are capable of slowing down the process of oxidation. Suitable antioxidants include, but are not limited to compound selected from the group consisting of citric acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium formaldehylde sulfoxylate, sodium metabisulfite, sodium thiosulfate, sulfur dioxide, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives.
Flavor enhancers are used to enhance the properties of flavoring agent used in the formulation. Suitable Flavor enhancer is citric acid.
Acidifying agents are used to reduce the pH of the final composition. Suitable acidifying agents include citric acid.
Swelling index is used to measure the water absorbing capacity of the laxatives. According to Indian pharmacopeial standards laxatives should have a swelling index of not less than 7 so as to have a desired biological efficacy. The final formulation has swelling index of about 16-17.
The invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
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EXAMPLE I:
Table I
Ingredients
% composition
Lactulose solution (64.0 to 69.3 % w/v solution)
50 % *
Isphagula Husk
17.5 %
Microcrystalline cellulose
21.0 to 22.0 %
Colloidal silicon dioxide
6.25 %
Aspartame
1.875 %
Sodium benzoate
1.25 %
Colour Quinoline Yellow
0.25 %
EDTA sodium
0.625 %
Flavor lemon powder
0.5 %
* 50 % composition is based on dried basis; in the manufacturing process, Lactulose solution (64.0 to 69.3 % w/v solution) is used. Accordingly input quantity is compensated so as to get lactulose of required composition in the formula.
Formulation process
Microcrystalline cellulose, colloidal silicon dioxide, Isphagula husk, aspartame, sodium benzoate and EDTA sodium are sifted through sieve # 40. Color quinoline yellow is sifted through sieve # 100.The above sifted materials are loaded into rapid mixer granulator and mixed for 5 to 10 minutes. Lactulose solution is added to the above dry mix with impeller ON at slow speed.The mass is mixed until granular mass is obtained. The granules are dried in a fluid bed dryer at an inlet temperature of 45 to 55° C until loss on drying is less than 2.0 % is obtained. The dried granules are sifted through sieve #20. The oversized granules are milled in a multimill fitted with 1.5 mm screen. Flavor lemon powder is sifted through sieve #40. The dried granules and sifted lemon flavor are loaded into an octagonal blender and mix for 5 to 10 minutes. The required quantity of granules is filled in HDPE container of suitable size and the containers are sealed.
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EXAMPLE II:
Formulation same as listed in Table I
Formulation process
Microcrystalline cellulose, Isphagula husk, aspartame, sodium benzoate and EDTA sodium are sifted through sieve # 40. Color quinoline yellow is sifted through sieve # 100. The above sifted materials are loaded into rapid mixer granulator and mixed for 5 to 10 minutes. Colloidal silicon dioxide is loaded in lactulose solution completely to get dispersion. Lactulose dispersion is added to the above dry mix with impeller ON at slow speed. The mass is mixed until granular mass is obtained. The granules are dried in a fluid bed dryer at an inlet temperature of 45 to 55° C until loss on drying is less than 2.0 % is obtained. Dried granules are sifted through sieve #20. The oversized granules are milled in a multimill fitted with 1.5 mm screen. Flavor lemon powder is sifted through sieve #40. Dried granules and sifted lemon flavor are loaded into a octagonal blender and mixed for 5 to 10 minutes. The required quantity of granules is filled in HDPE container of suitable size and the containers are sealed.
EXAMPLE III:
Table II
Ingredients
% composition
Lactulose solution (64.0 to 69.3 % w/v solution)
50 % *
Isphagula Husk
17.5 %
Microcrystalline cellulose
21.0 to 22.0 %
Colloidal silicon dioxide
6.25 %
Aspartame
1.875 %
Sodium benzoate
1.25 %
Colour Quinoline Yellow
0.25 %
Citric acid
0.5 to 1.0 %
Flavor lemon powder
0.5 %
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* 50 % composition is based on dried basis; in the manufacturing process, Lactulose solution (64.0 to 69.3 % w/v solution) is used. Accordingly input quantity is compensated so as to get lactulose of required composition in the formula.
Formulation process
Microcrystalline cellulose, colloidal silicon dioxide, Isphagula husk, aspartame, sodium benzoate and citric acid are sifted through sieve # 40. Color quinoline yellow is sifted through sieve # 100. The above sifted materials are loaded into rapid mixer granulator and mixed for 5 to 10 minutes. Lactulose solution is added to the above dry mix with impeller ON at slow speed. The above mixture is mixed until granular mass is obtained. The granules are dried in a fluid bed dryer at an inlet temperature of 45 to 55° C until loss on drying is less than 2.0 % is obtained. The dried granules are sifted through sieve #20. The oversized granules are milled in a multimill fitted with 1.5 mm screen. Lemon powder is sifted through sieve #40. The dried granules and sifted lemon flavor are loaded into an octagonal blender and mixed for 5 to 10 minutes. The required quantity of granules is filled in HDPE container of suitable size and the containers are sealed.
EXAMPLE IV:
Formulation same as listed in Table II
Formulation process
Microcrystalline cellulose, Isphagula husk, aspartame, sodium benzoate and citric acid are sifted through sieve # 40. Quinoline yellow is sifted through sieve # 100. The above sifted materials are loaded into rapid mixer granulator and are mixed for 5 to 10 minutes. Colloidal silicon dioxide is dispersed in lactulose solution completely in order to get a uniform dispersion. The lactulose dispersion is added to the above dry mix with impeller ON at slow speed. The mass is mixed until granular mass is obtained. The granules are dried in a fluid bed dryer at an inlet temperature of 45 to 55° C until loss on drying is less than 2.0 %. The dried granules obtained are sifted through sieve #20. The oversized granules are milled in a multimill fitted with 1.5 mm screen. Flavor lemon powder is sifted through sieve #40. The dried granules and sifted lemon flavor are loaded into a octagonal blender and mixed for 5 to 10 minutes. The required quantity of the final blend is filled in HDPE container of suitable size and the containers are sealed.
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We claim
1. Process of preparation of granules comprising lactulose and isphagula husk wherein lactulose is used optionally in combination with adsorbents or suspending agent for granulating the mixture of isphagula husk with other excipients.
2. Process according to claim 1, in which lactulose is used optionally in combination with adsorbents or suspending agent for granulating the mixture of isphagula husk and microcrystalline cellulose with other excipients.
3. Process according to any of the preceding claims wherein lactulose is optionally in solution form.
4. Process according to preceding claims wherein excipients include diluent, adsorbent and suspending agent, sweetner, flavoring agent, preservative, colorant, stabilizer, flavor enhancer, antioxidant and acidifying agent.
5. Process according to any of the preceding claims wherein the granules prepared are dried using fluid bed dryer.
6. Process according to claim 4, wherein diluents is selected from the group consisting of microcrystalline cellulose, lactose, starch, sucrose, polysaccharides, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, and dextrins and mixtures thereof.
7. Process according to claim 4, wherein adsorbent and suspending agent is selected from the group consisting of colloidal silicon dioxide, natural or synthetic gums, resins, methylcellulose and sodium carboxymethylcellulose.
8. Process according to claim 4, wherein sweetner is selected from the group consisting of aspartame, saccharin, sucralose, neotame, and acesulfame potassium.
9. Process according to claim 4, wherein flavoring agent is selected from the group consisting of Lemon flavor, orange flavor, pineapple flavor, strawberry flavor, raspberry flavor, mixed fruit flavor.
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10. Process according to claim 4, wherein preservative is selected from the group consisting of, sodium benzoate, methyl paraben and propyl paraben.
11. Process according to claim 4, wherein colorant is selected from the group consisting of Tartrazine, quinoline yellow, sunset yellow, Ponceau 4R, erythrosine, carmoisine.
12. Process according to claim 4, wherein stabilizer is selected from the group consisting of EDTA sodium and citric acid.
13. Process according to claim 4, wherein antioxidant or flavor enhancer or acidifying agent is citric acid.
14. Process according to claim 1, wherein lactulose acts as a binder for the preparation of granules.
15. A method for the treatment of patients with constipation includes administering an effective amount of granular composition comprising lactulose, isphagula husk and microcrystalline cellulose.

Dated this 29th day of October, 2009

P.H.D.Rangappa
IN/PA-1538
Of K & S Partners
Agent for the Applicant