A tablet formulation of combined vitamins b1, b6, and b12

Abstract

The present invention relates to an oral solid dosage form comprising a combination of multiple water-soluble vitamins, specifically Vitamin B1, Vitamin B6, and Vitamin B12. It discloses a novel method for manufacturing a delayed-release tablet formulation designed to maintain a consistent and satisfactory in vitro dissolution profile throughout its shelf-life. This unique formulation ensures the stability and bioavailability of the vitamins, providing an effective means for improving health.

Description

[0001] A TABLET FORMULATION OF COMBINED VITAMINS B1, B6, AND B12

[0002] DESCRIPTION

[0003] Technical field:

[0004] The present invention discloses an oral solid dosage form featuring multiple water- soluble vitamins. It describes a method for manufacturing a delayed release Vitamin B1- B6-B12 tablet that maintains a consistent and satisfactory in vitro dissolution profile over its shelf-life. The combined vitamin B composition is effective for improving health.

[0005] Prior Art:

[0006] Vitamins are essential nutrients that must be provided to the body in small amounts on a regular basis to enable the performance of various chemical and physiological functions within the human body. Although vitamins are a group of organic compounds that exhibit diverse structural and chemical properties, they can be conveniently classified into two categories based on their solubility: fat-soluble vitamins and water- soluble vitamins. The former category comprises vitamins A, D, E, and K, as well as other carotenoids with varying degrees of vitamin A activity. The latter category is composed of vitamin C and eight B vitamins, namely thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pyridoxine (vitamin B6), pantothenic acid (vitamin B5), biotin (vitamin B7), folate (vitamin B9) and cyanocobalamin (vitamin B12).

[0007] While a balanced diet can readily meet the vitamin requirements of the human body, certain populations are more vulnerable to low micronutrient intake and consequently face a heightened risk of vitamin deficiency. In the absence of adequate levels of these nutrients, biological processes are unable to function correctly, resulting in the development of avitaminosis. The administration of specific vitamins and minerals has been demonstrated to confer protection against disease and contribute to overall health.

[0008] Vitamins B1 , B6 and B12 are believed to play a role in the human endogenous metabolism, and they are present in small quantities in natural food sources. B vitamins are essential for many aspects of the body's functioning, but they have been closely tied to both hormone metabolism and neurologic development and function. The a- vitaminosis B are typically attributed to nutritional deficiencies, competition between bacteria, disturbances of the intestinal flora, and excessive sun exposure. Multivitamin tablets are frequently employed in therapeutic management, in the context of inadequate dietary intake, and for the purpose of fortification.

[0009] Vitamin B1 (thiamine) was initially isolated in 1926 and subsequently characterised in the 1930s. It was the first water-soluble vitamin to be structurally characterised and was formally assigned the designation vitamin B1 by the British Medical Research Council in 1927. The compound is constituted of a pyrimidine ring (4-amino-2-methylpyrimidinyl-5- ylmethyl) linked to the 3-nitrogen atom in a substituted thiazole moiety (5-(2- hydroxyethyl)-4-methylthiazole) via a methylene bridge. Deficiencies in vitamin B1 correlate with a neurological disorders such as Wernicke syndrome and Korsakoff syndrome wherein neurologic function is impaired. Vitamin B1 deficiency is also associated with muscle weakness and the nutritional deficiency disease Beriberi.

[0010] Vitamin B6 (pyridoxine) was initially identified by Gyorgy in 1934 as a distinct therapeutic agent from riboflavin and niacin for a particular dermatitis in rats. He designated the compound as pyridoxine, which was subsequently isolated and structurally characterised by several researchers in the late 1930s. Subsequent research identified additional derivatives of pyridoxine, including pyridoxal and pyridoxamine, which also exhibited vitamin B6 activity in 1944. The term "vitamin B6" is a generic descriptor for all derivatives of 3-hydroxy-2-methylpyridine that are referred to as vitamin B6 vitamers and demonstrate the same biological activity as pyridoxine (PN) in rats. The term PN is typically used interchangeably with vitamin B6. It is one of three naturally occurring forms, the others being pyridoxal (PL) and pyridoxamine (PM). They can exist in either a free or a phosphorylated form and be bound to proteins. These three forms are interconvertible and considered to be biologically active equivalents, undergoing enzymatic phosphorylation and conversion to the metabolically active pyridoxal-5- phosphate (PLP). The ultimate product of vitamin B6 metabolism, 4-pyridoxic acid (4- PA), is also a common form that occurs naturally in biological samples. Another significant form is the glucosidically bound form of PN (PN glucoside), which has a low bioavailability and is exclusively present in plant sources. Additionally, research conducted by scientists at the International Agency for Research on Cancer in Lyon, France has demonstrated that vitamin B6 and methionine are strongly associated with a reduction in lung cancer risk in individuals who have never smoked.

[0011] Vitamin B12 (cobalamin) is a coordination complex of cobalt, which occupies the centre of a corrin ligand and is further bound to a benzimidazole ligand and an adenosyl group. This designation encompasses any member of the cobalamin family of cobalt-containing compounds, which includes, but is not limited to, cyanocobalamin, hydroxocobalamin, methylcobalamin, and 5-deoxyadenosylcobalamin. Cyanocobalamin was first produced in the 1940s. In 2022, it was the 131st most commonly prescribed medication in the United States, with a total of over four million prescriptions. It is essential for the optimal functioning of the brain and nervous system, as well as for the production of blood. It is involved in the metabolism of every cell in the body, with a particular impact on the synthesis and regulation of DNA, as well as on fatty acid synthesis and energy production.

[0012] The research team at the Jean Mayer USDA Human Nutrition Center on Aging at Tufts University has a particular interest in the effects of vitamin B6 and vitamin B12. The researchers have discovered that metabolic impairments resulting from a diet deficient in vitamin B12 and vitamin B6 led to cognitive dysfunction and reductions in brain capillary length and density in a mouse model. This evidence suggests that B vitamin deficiency may play a role in the development of Alzheimer's disease. This vitamin, which contains cobalt, is synthesised by microorganisms and exists in different chemical forms in foods of animal origin, including milk, cheese and eggs, as well as in artificially fortified foods. It is essential for overall metabolism, the function of the nervous system, the metabolism of folic acid, and the production of red blood cells. Consequently, vitamin B12 deficiency (either quantitative or functional) results in the accumulation of homocysteine and methylmalonic acid (MMA) in plasma. Cyanocobalamin is the most stable and widely utilised form of vitamin B12. It is attached to plasma proteins and stored in the liver. Vitamin B12 is excreted in the bile and undergoes enterohepatic recycling. The absorbed vitamin B12 is transported via specific B12 binding proteins, transcobalamin I and II, to the various tissues. The liver is the primary organ responsible for vitamin B12 storage.

[0013] Vitamin B12 deficiency can result in the development of neuropathy, even in the absence of anaemia. A vitamin B12 deficiency may occur in individuals who adhere to a vegan diet, as vegetables are not a significant source of this vitamin. To address this deficiency, some vegans may opt for dietary supplements, such as tablets and capsules.

[0014] EP 2255803B1 discloses a solid oral pharmaceutical composition comprising the combination of ketorolac and B-complex, which includes, inter alia, thiamin, pyridoxine and cyanocobalamin (vitamins B1 , B6 and B12, respectively), and / or the pharmaceutically acceptable salts thereof.

[0015] In light of the pivotal role of B vitamins in the prevention of neurological and other disorders, there is a continued necessity for combined vitamin B supplements that effectively release B vitamins in vitro. The formulation of water-soluble vitamins for shelf- life conditions represents a distinctive challenge, largely attributable to the intricate matrices in which they are typically found. The development of multivitamin compounds with a favourable release profile is therefore of both importance and challenge.

[0016] The present invention proposes a composition intended for the treatment of vitamin B deficiency comprising vitamins B1 , B6 and B12. It offers a solution to the manufacturing of a delayed-release vitamin B1-B6-B12 tablet that maintains a consistent and satisfactory in vitro dissolution profile.

[0017] It is therefore desirable to provide a pharmaceutical composition which, in addition to releasing the entire active ingredient, provides a delayed release of the active ingredient while maintaining the desired release profile throughout the shelf life. Moreover, it is crucial to develop a straightforward pharmaceutical composition that can be readily prepared and maintained in vitro over its shelf life, while preserving its beneficial solubility and bioavailability properties, particularly from the patient compliance perspective.

[0018] Description of the Invention:

[0019] The objective of the present invention is to produce a delayed release Vitamins B1 , B6, B12 Tablet and a preparation method thereof.

[0020] The present invention relates to formulate a pharmaceutical and effective oral delayed release tablet composition comprising about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12, wherein maintaining the desired release throughout the shelf life.

[0021] The present invention relates to a delayed release system in the form of an enteric coated tablet comprising about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12, wherein the coating comprises one or more film-forming polymers for retention of the release in the stomach.

[0022] According to one embodiment of the present invention, the pharmaceutical tablet composition comprising about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12 comprised of 4% to 6% polymer based binder and 5% to 7% polymer based enteric coating by weight based on total weight of the composition.

[0023] According to another embodiment of the present invention, the pharmaceutical tablet composition comprising about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12 comprised of 4% to 6% average molecular weight of 500,000 dalton and larger povidone and 5% to 7% Eudragit based enteric coating by weight based on total weight of the composition.

[0024] According to another embodiment of the present invention, the pharmaceutical tablet composition comprising about 250 mg of thiamin hydrochloride monohydrate, about 250 mg of pyridoxine hydrochloride, and about 1000 pg of cyanocobalamin comprised of 4% to 6% average molecular weight of 500,000 dalton and larger povidone and 5% to 7% Eudragit based enteric coating and a sub-coating with a weight percentage of 2% by weight based on total weight of the composition

[0025] The B vitamins comprise one or more of the following: vitamin B1 , vitamin B2, vitamin B3 (nicotinamide form), vitamin B5, vitamin B6, vitamin B7, vitamin B12, vitamin Bt (carnitine), vitamin Benfotiamine, and vitamin Bx (PABA). The current composition employs B-complex vitamins, which are both hydrosoluble and liposoluble, exhibiting a pH range of 3.0 to 5.0. These vitamins are highly photosensitive and generally susceptible to environmental stimuli.

[0026] The present invention employs the use of vitamins B1 , B6, and / or B12, which are classified as hydrosoluble vitamins. The utilization of these vitamins does not preclude the potential for the inclusion of other vitamins within the B-complex.

[0027] The B-complex (comprising vitamins B1 , B6 and / or B12) has a number of therapeutic applications, including the treatment of vitamin deficiencies, as well as conditions occurring in a pre- or post-operative state, such as neuritis, polyneuritis, chronic diarrhoea, polyneuropathies and Wernicke encephalopathy.

[0028] In another embodiment, the compositions may include vitamin B1 in the form of one or more of the following: thiaminhydrochloride, thiamin pyrophosphate (TPP), thiamin monophosphate (TMP), and thiamin diphosphate (TDP). In the present invention, the vitamin B1 is thiamin hydrochloride or pharmaceutically acceptable hydrates, specifically thiamin hydrochloride monohydrate.

[0029] In another embodiment, the compositions may include vitamin B6 in the form of pyridoxine hydrochloride (PN.HCI), pyridoxal hydrochloride (PL.HCL) or pyridoxamine dihydrochloride (PM.2HCI), as selected. In the present invention, the vitamin B6 is in the form of pridoxine hydrochloride.

[0030] In another embodiment, the compositions may include vitamin B12 in the form selected from one or more of the group consisting of cobalamin, methylcobalamin, 5'- deoxyadenosylcobalamin (adenosylcobalamin or cobalaminamide), cyanocobalamin, hydroxycobalamin and mecopalamine. In the present invention, the vitamin B12 is cyanocobalamin.

[0031] The following section presents a summary of the clinical scenarios in which the tablet dosage form containing vitamin B1 , B6 and B12, developed in the present invention, may be employed in patients at risk of vitamin B1 , B6 and B12 deficiency.

[0032] The tablet dosage form containing vitamin B1-B6-B12 is indicated for patients presenting with general clinical symptoms such as mental and physical fatigue, forgetfulness, irritability, weakness, tremors, neuritis, polyneuritis, diabetic neuropathy, neuralgia, shingles, tremors, and other painful conditions such as arthritis, periarthritis. Furthermore, the tablet dosage form containing vitamin B1-B6-B12 is indicated for the treatment of sciatica, lumbalgia, arthralgia, myalgia, cramps and rheumatic pains.

[0033] Additionally, it is used as an adjunct in the treatment of cardiomyopathy, vomiting after surgery, radiation sickness, febrile rheumatism and chronic intoxication, especially during alcoholism.

[0034] The objective of formulating a compound into a tablet or other solid dosage form is to develop oral modified-release formulations that will improve tolerability and adherence to treatment.

[0035] A storage-stable formulation that can withstand temperatures and relative humidity levels above those typically encountered. Furthermore, the formulation should be designed to exhibit additional desirable properties, such as delayed release dissolution. This ensures that the tablet does not dissolve in an acidic medium and dissolves in a basic medium, thereby facilitating the availability of the drug for absorption. Accordingly, the objective of the present invention is to exhibit good storage stability and delayed release dissolution. The present invention has yielded a stable and solid oral pharmaceutical composition comprising vitamins B1 , B6 and B12.

[0036] Pharmaceutical companies are dedicated to the pursuit of enhanced product quality and accelerated drug development, while concurrently pursuing innovative strategies for the reduction of costs. The production of compressed tablets can be achieved through three principal processes: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and the selection of excipients are meticulously chosen in order to achieve the desired physical characteristics of the tablet formulation, thus enabling the efficient compression of the tablets. In one aspect, the invention pertains to a pharmaceutical composition prepared via wet granulation. Granulation is the process by which primary particles (powders) are made to adhere and form larger, multiparticulate entities, known as granules. Granulation is typically initiated following the initial dry mixing of the powdered ingredients, with the objective of ensuring a uniform distribution of the ingredients throughout the mixture. Granulation methods can be classified into two principal categories: those that employ a liquid medium to facilitate granule formation (wet granulation) and those that do not (dry granulation).

[0037] Wet granulation entails the aggregation of the primary powder particles with the aid of a granulating fluid. The fluid contains a solvent that can be removed by drying and is nontoxic. The granulating fluid may be employed as a standalone agent or, more commonly, in conjunction with a binding agent (binder) to guarantee the adhesion of the final product in the dry state. Binding agents can be incorporated into the system in two ways: as a binder solution (as part of the granulating fluid) or as a dry material mixed with the primary powder particles. The principal categories of wet granulator are shear granulators, high shear mixer granulators and fluid bed granulators.

[0038] High shear wet granulation is a process that involves the intensive dry mixing of primary powders and the subsequent addition of a granulating fluid, resulting in the formation of granules. The granulating fluid comprises a volatile solvent (typically water) and may also contain a binder, which is responsible for ensuring particle adhesion. Additionally, binders may be incorporated into the bulk of the formulation to be granulated in a dry powder form. The use of granules presents a number of advantages over the use of powders. These include improved flow properties, a reduced risk of segregation and increased homogeneity. (Source: Aulton ME, Pharmaceutics- The Science of Dosage Form Design, 2nd Edition, 2002, Churchill Livingstone)

[0039] The term "vitamin" encompasses a naturally occurring vitamin, a vitamin precursor, a salt derivative of a vitamin, a vitamin ester, or a metabolite thereof, in either a natural or synthetic form. Examples of vitamins that may be included in the formulations described herein include, but are not limited to, B vitamins, specifically vitamin B1 , vitamin B6, and vitamin B12, or their pharmaceutically acceptable salts.

[0040] The term "active substance" or "active pharmaceutical ingredient" is defined as any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human body or other animals. In the present invention, the active substance is B vitamins, specifically vitamin B1 (thiamin hydrochloride), vitamin B6 (pyridoxine hydrochloride), and vitamin B12 (cyanocobalamin).

[0041] In this context, the term "dosage form" refers to the specific manner in which the dose is to be administered to the subject or patient. The drug or supplement is typically administered in conjunction with other non-medical agents as part of a formulated regimen. The dosage form possesses distinctive physical and pharmaceutical attributes. The dosage forms may be classified as solid, liquid, or gaseous. The term "dosage form" encompasses a multitude of forms, including but not limited to capsules, tablets, caplets, gel caplets (also known as gelcaps), syrups, liquids, powders, concentrated powders, concentrated powder admixed with liquids, chewable forms, swallowable forms, dissolvable forms, effervescent forms, granulated forms, and oral liquid solutions. In a particular instance, the dosage form is in the form of a tablet.

[0042] In another specific embodiment, the tablet dosage form comprises about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12.

[0043] In this context, the term "pharmaceutically acceptable" is used to describe those compounds, materials, compositions and / or dosage forms that are suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other complications commensurate with a reasonable benefit / risk ratio.

[0044] In addition to the active or therapeutic substances, tablets contain a number of inert materials, known as excipients, which are essential for their function. It should be noted that the pharmaceutical compositions described herein may include one or more pharmaceutically acceptable excipients, if desired. The term "excipient" is used to describe any substance that is not itself a therapeutic agent. It can be employed as a carrier or vehicle for the delivery of a therapeutic agent to a subject. Furthermore, it can be combined with a therapeutic agent (e.g. to create a pharmaceutical composition) in order to enhance its handling or storage properties. Furthermore, it can be employed to permit or facilitate the formation of a dose unit of the composition. Excipients may be broadly classified into the following categories: binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralising agents, if necessary), penetration enhancers, solubilising agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odour, fragrances or taste, and substances added to improve the appearance or texture of the composition. The aforementioned excipients may be employed in any dosage forms, as outlined in the present disclosure. It is to be expected that a person of ordinary skill in the art would recognise that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of the Vitamin B1 , Vitamin B6 and Vitamin B12 tablet composition.

[0045] The present invention concerns an oral solid dosage form comprising vitamins B1 , B6 and B12 and at least one excipient. It is preferable that the vitamin B1 , B6 and B12 tablet comprises at least one binder, at least one filler (diluent), at least one disintegrant and at least one lubricant. The excipients can be classified according to their function within the final tablet. Excipients are typically incorporated into a formulation to facilitate the flow and compression characteristics of the material being compressed.

[0046] The filler (diluent) is added with the objective of increasing the bulk weight of the blend, thereby facilitating the practical size for compression. In accordance with one embodiment of the invention, the composition comprises at least one filler (diluent) selected from the group comprising microcrystalline cellulose, lactose, mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, and so forth. Additionally, the composition may comprise calcium salts, polysaccharides, inorganic phosphates (such as dibasic calcium phosphate), sodium chloride, dextrates, lactitol, maltodextrin, a sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or a combination thereof. In the present invention, mannitol is selected as the excipient.

[0047] The binders serve the function of agents, imparting cohesive qualities to the powdered material. In accordance with one embodiment of the invention, the composition comprises at least one binder selected from the group comprising polyvinyl pyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacrylate, or mixtures thereof. In the present invention, polyvinyl pyrrolidone (Povidone) has been selected as the binder.

[0048] The inclusion of disintegrants serves the purpose of decomposing the tablet in the gastrointestinal fluid, thereby ensuring that the tablet exhibits an acceptable rate of disintegration. In accordance with one embodiment of the invention, the composition comprises at least one disintegrant, selected from the following group: croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycollate. The other components include starch, pregelatinised starch, alginic acid and alginates, ion exchange resins, magnesium aluminium silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof. In the present invention, pregelatinised starch is selected as the disintegrant.

[0049] The lubricant is typically added for the purpose of preventing the tableting materials from adhering to punches, reducing friction during the compression of tablets, and facilitating the removal of the compressed tablet from the die. Such lubricants are typically incorporated into the final tablet mixture in quantities ranging from 0.5% to 2.5% by weight. The composition comprises at least one lubricant selected from the group comprising magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and sodium stearyl fumarate, or mixtures thereof. In the present invention, magnesium stearate is selected as the lubricant of choice.

[0050] The term "rate-controlling polymer" as used herein encompasses hydrophilic polymers, hydrophobic polymers, and mixtures of hydrophilic and / or hydrophobic polymers that are capable of regulating or retarding the release of the peptide or protein from a solid oral dosage form of the present invention. Suitable rate-controlling polymer materials include those selected from the group consisting of hydroxyalkyl cellulose, such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; poly(ethylene) oxide; alkyl cellulose, such as ethyl cellulose and methyl cellulose; carboxymethyl cellulose; hydrophilic cellulose derivatives; and polyethylene glycol. Polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinyl acetate phthalate; hydroxypropylmethyl cellulose phthalate; hydroxypropyl methyl cellulose acetate succinate; polyvinyl acetaldiethylamino acetate; poly(alkylmethacrylate) and poly(vinyl acetate). Other suitable hydrophobic polymers include polymers and / or copolymers derived from acrylic or methacrylic acid and their respective esters, Zein, waxes, shellac and hydrogenated vegetable oils. Of particular utility in the practice of the present invention are polyacrylic acid, polyacrylate, polymethacrylic acid, and polymethacrylate polymers, including those sold under the Eudragit tradename (Rohm GmbH, Darmstadt, Germany), specifically Eudragit L, Eudragit S, Eudragit RL, and Eudragit RS coating materials, as well as mixtures thereof. Some of these polymers can be employed as delayed-release polymers, facilitating the regulation of the site at which the drug is released. Such polymers include polymethacrylate polymers, which are available under the Eudragit tradename (Rohm GmbH, Darmstadt, Germany). The pharmaceutical dosage form, as described in this invention, comprises vitamin B1 , vitamin B6, and vitamin B12 in tablet form, coated with both a sub-coating and a polymer coating material. The specific coating materials are not limited and are known to those with the requisite technical expertise.

[0051] The selection of suitable excipients for a specific active ingredient and the determination of an appropriate manufacturing process for the combination of excipient and active substance represent a significant challenge in the design of a pharmaceutical product such as a tablet.

[0052] Furthermore, it is essential to consider additional desirable properties, such as delayed release dissolution, to guarantee that the drug is available for absorption. The present invention achieves delayed release dissolution over the product's shelf life, in addition to other highly desirable characteristics.

[0053] Examples:

[0054] The scope of present invention is the preparation of a pharmaceutical tablet dosage form for oral administration comprising vitamin B1 , vitamin B6, and vitamin B12.

[0055] Example 1. Compositions prepared by wet granulation process

[0056] The formulation development studies commenced with an investigation of the physical properties, chemical properties, solubility and pharmacokinetic properties of the B1 , B6 and B12 vitamins. The properties of the final product were determined by considering the content and in vitro release profile of the reference product formulation.

[0057] In the case of delayed-release vitamin B tablets, the percentage of enteric coating and binder that control the release are critical parameters. Given that the most crucial parameters in the current composition are the percentage of enteric coating and binder employed, a series of varying percentages of enteric coating and binder were applied to the prepared tablets. Table 1. Unit formula for vitamins B1 , B6 and B12 Tablet

[0058] % Component

[0059] F-01 F-02 F-03 F-04 F-05 F-06

[0060] Tiamin HCI.I H2O 41 .7 41.7 41 .7 41.7 41.7 41.7

[0061] Pyridoxin HCI 41.7 41.7 41.7 41.7 41.7 41.7

[0062] Cyanocobalamin 0.2 0.2 0.2 0.2 0.2 0.2

[0063] Mannitol 6.4 6.4 4.4 4.4 4.4 4.4

[0064] Povidon 3 3 5 5 5 5

[0065] Pregelatinised 5 5 5 5 5 5 starch

[0066] Colloidal silicon dioxide

[0067] Magnesium

[0068] Sub-coating 2 2 2 2 2 2

[0069] Copolymer enteric _7. _7 acoat ..ing 0 I 4 0 1 y

[0070] A tablet composition was prepared in accordance with the specifications outlined above, ensuring the inclusion of the requisite quantities of active substances and excipients. Upon completion of the wet granulation process, the granules were compressed into tablets using appropriate tooling. The tablets were subsequently subjected to a subcoating and copolymer enteric coating.

[0071] In the studies on the amount of binder, it was observed that the product was released in an acidic medium in studies where the amount of binder was 3% (F-01 and F-02). This resulted in the expected profile not being obtained due to the dissolution exceeding 10% in the in vitro dissolution study in acidic medium. Accordingly, the 3% binder content was found to be inadequate for the product. In subsequent studies, the quantity of binder was augmented to 5%. In finished products where the enteric coating was 4% (F-03), the delayed release properties could not be achieved, with rapid release occurring at pH 6.8 due to insufficient enteric coating. It was thus determined that the desired profiles could be obtained with an amount of binder above 3% and an amount of enteric coating above 4%. When the enteric coating was 9% (F-06), the release at pH 6.8 was not as desired (low release was observed).

[0072] The studies revealed that the average molecular weight of the povidone employed was also a crucial factor. It was observed that when povidone with an average molecular weight of approximately 50,000 Dalton was employed in the studies, the release in a pH 6.8 environment could not be regulated, resulting in a rapid release. In order to achieve the desired release profiles, it was determined that the use of polymers with an average molecular weight of 500,000 Dalton or greater would be necessary.

[0073] Example 2. In-vitro Dissolution Studies

[0074] The rate of systemic absorption is dependent upon the dissolution of the drug in question. A variety of in vitro methods have been developed for the assessment of the dissolution properties of pharmaceutical formulations. Dissolution testing is sometimes employed as a surrogate for the direct evaluation of drug bioavailability (Source: Emmanuel et al., Pharmaceutics, 2010, 2:351-363). Dissolution testing entails the measurement of the percentage of the active substance released from the drug product (i.e., tablet or capsule) and dissolved in the dissolution medium under controlled testing conditions over a defined period of time. In order to maintain sink conditions, the saturation solubility of the drug in the dissolution medium should be at least three times the drug concentration. In the case of compounds with low solubility, dissolution may be determined under nonsink conditions on occasion. The dissolution process is influenced by a number of factors, including the intrinsic properties of the active substance (e.g., particle size, crystal form, bulk density), the composition of the drug product (e.g., drug loading, excipients), the manufacturing process (e.g., compression forces) and the stability of the drug product under storage conditions (e.g., temperature, humidity).

[0075] The in-vitro dissolution profile of Formulation Trials (F-01 to F-06) was recorded in an acidic medium (0.1 N HCI) for a period of two hours and in buffer medium (pH 6.8 HCI) for a period of three hours. This was conducted at 75 rpm in a 900 mL paddle apparatus, with the results then compared to those of the reference product (Benexol B12 Film Coated Tablet). An in vitro comparative dissolution test was conducted for the test and reference products in accordance with the Guideline on Investigation of Bioequivalence. The chosen dissolution conditions were as follows: 900 mL dissolution medium, paddle at 75 rpm at 37°C ± 0.5°C at 0.1 N HCI for 2 hours and buffer pH 6.8 HCI for 3 hours. The aforementioned compositions (Formulations F-01 to F-06), comprising vitamins B1 , B6 and B12, were subjected to an in vitro evaluation and compared with a commercially available reference product, namely the Benexol B12 Film Coated Tablet.

[0076] A delayed release vitamins B1 , B6 and B12 Tablet should have a dissolution rate of releasing maximum of 10% at 0.1 N HCI at the end of 120 minutes and releasing more than 70% at pH 6.8 buffer at the end of 180 minutes. In the present invention, in vitro dissolution results of formulas F04 and F05 were within the desired ranges (Figure 1). Example 3. Stability Studies

[0077] The stability of a drug product is a crucial consideration in the manufacture of safe and efficacious pharmaceutical products. Stability issues may be caused by environmental factors, including humidity and temperature. The physical and chemical stability of a drug product may be evaluated through conventional analytical techniques, including the measurement of physical attributes such as appearance, water content, and assay, as well as in vitro release and microbiological assessments.

[0078] In the development of the tablet dosage form, the stability of the product was assessed under 25°C±2°C storage condition in temperature-programmable control cabinets. A temperature of 25°C ± 2°C and a relative humidity of 60%±5% RH (relative humidity) represents the ambient condition. The tablets of the invention were found to remain stable under a variety of conditions, including those involving conventional packaging, such as sealed PVC / PE / PVdC / Alu blisters.

[0079] Conversely, the stability of vitamins is influenced by the storage environment, including pH, light, heat, and moisture. However, the content is also reduced by the presence of other components, such as additives and different types of vitamins. Furthermore, the stability of a given vitamin is contingent upon the dosage form selected and the specific vitamin component employed in the preparation of a medicinal vitamin. Consequently, when developing a vitamin-containing formulation, the manufacturing process, shape, and vitamin component are selected based on considerations of productivity, ease of administration, and absorption, while ensuring stability within the parameters of the approval criteria.

[0080] According to the stability studies, the results of the products stored for 12 months at 25°C±2°C stability condition proved that the results of the in vitro dissolution studies were appropriate and that the product maintained its release profiles throughout its shelf life.

[0081] The present invention outlines a method for the production of a delayed-release vitamin B complex tablet that exhibits a consistent and satisfactory in vitro dissolution profile over its shelf life.

[0082] FIGURES

[0083] Figure 1. Comparison of in vitro dissolution profile for Test product (F-03 - F-06) and Reference product (Benexol B12 Tablet)

Claims

CLAIMS1. A pharmaceutical composition for oral administration comprises about 250 mg of vitamin B1 , about 250 mg of vitamin B6, and about 1000 pg of vitamin B12 wherein the said composition comprises 4% to 6% polymer based binder and 5% to 7% polymer based enteric coating by weight based on total weight of the composition.

2. The composition of claim 1 , wherein the polymer based binder is povidone.

3. The composition of claim 3, wherein the composition comprises average molecular weight of 500,000 dalton and larger povidone.

4. The composition of claim 1 , wherein the polymer based enteric coating is Eudragit based enteric coating.

5. The composition of claim 1 , wherein said pharmaceutical composition is in the form of a tablet.

6. The composition of claim 5, wherein said tablet further comprises at least one of an excipient carrier, filler, filler / diluent, diluent, disintegrating agent, emulsifier, glidan, lubricant, stabiliser, sweetener, flavouring agent, colouring agent, solubilising agent or combinations thereof.

7. The composition of claim 1 , wherein the vitamin B1 is thiamin hydrochloride monohydrate.

8. The composition of claim 1 , wherein the vitamin B6 is pyridoxine hydrochloride.

9. The composition of claim 1 , wherein the vitamin B12 is a cyanocobalamin.

10. The composition of claim 1 , wherein the composition comprises a sub-coating.

11. The composition of claim 1 , wherein the said tablet comprises a sub-coating with a weight percentage of 2% based on the total weight of the composition.

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