WO2019145926A1

WO2019145926A1 - Stable thiamine containing pharmaceutical formulations

Info

Publication number: WO2019145926A1
Application number: PCT/IB2019/050690
Authority: WO
Inventors: Sau Hung LEUNG; Xinran Zhang; Chi Tak Wong; Junmin Wang
Original assignee: Fortune Pharmacal Company Limited
Priority date: 2018-01-29
Filing date: 2019-01-29
Publication date: 2019-08-01
Also published as: CN111655263A

Abstract

Pharmaceutical formulations containing thiamine and their manufacturing methods are provided. Various formulations further incorporate a local concentration of citric acid to control the pH of the formulations, and thus enhance the stability of thiamine, while maintaining the same overall formulation composition. The formulations may be multilayer structures and citric acid and thiamine may be contained within the same layer to promote thiamine stability. Various formulations may further exclude alkaline constituents from the thiamine containing layer.

Description

STABLE THIAMINE CONTAINING PHARMACEUTICAL FORMULATIONS

FIELD OF THE INVENTION

[0001] The invention relates to pharmaceutical formulations, and more particularly to thiamine (Vitamin Bi) stabilized pharmaceutical formulations.

BACKGROUND OF THE INVENTION

[0002] Thiamine is used in a number of pharmaceutical formulations. Thiamine is often included because it has little to no side effects and may have several beneficial uses for a variety of conditions. For example, thiamine may improve immune function, reduce viral infection, and reduce the onset of cervical cancer or AIDS. Thiamine may reduce cataracts, glaucoma and other vision problems. Thiamine may reduce stress and improve heart function. Thiamine may reduce the onset of kidney disease in individuals having diabetes. Thiamine may prevent dysmenorrhea (painful menstruation). Thiamine may also increase appetite and/or reduce motion sickness.

[0003] Many cold and allergy remedies, for example, contain thiamine, which also often include antihistamines, such as, for example, chlorpheniramine maleate, and decongestants, such as, for example, phenylephrine hydrochloride. Despite the efficacious nature of these formulations thiamine is often unstable and degrades over time.

BRIEF SUMMARY OF THE INVENTION

[0004] Many embodiments are directed to pharmaceutical compositions utilizing thiamine. Several embodiments of pharmaceutical compositions further include an acidic buffer reagent. Embodiments are also directed to pharmaceutical compositions that compartmentalize thiamine in a layer that is exclusive of alkaline ingredients.

[0005] In an embodiment, a formulation for mitigating thiamine instability includes a multilayer tablet that includes thiamine, an acidic buffering agent and an alkaline ingredient. The thiamine and the alkaline ingredient are compartmentalized in separate layers. [0006] In another embodiment, the acidic buffering agent is compartmentalized to the thiamine containing layer.

[0007] In yet another embodiment, the acidic buffering agent is a citric acid, acetic acid, ascorbic acid, tartaric acid, fumaric acid, carbonic acid, bicarbonate, phosphoric acid, hydrochloric acid or monopotassium phosphate.

[0008] In a further embodiment, the acidic buffering agent is citric acid monohydrate.

[0009] In still yet another embodiment, the relative size of the thiamine containing layer as compared to the total tablet size is 100%, 75%, 66%, 50%, 33%, 25%, 20%, 15%, or 10%.

[0010] In an even further embodiment, the relative size of the thiamine containing layer as compared to the total tablet size is 50%.

[0011] In still yet an even further embodiment, the relative size of the thiamine containing layer as compared to the total tablet size is 25%.

[0012] In still yet an even further embodiment, compartmentalization of the acidic buffering agent increases its local concentration within the thiamine containing layer while the total concentration of the acidic buffering agent for the whole multilayer tablet remains constant.

[0013] In still yet an even further embodiment, the formulation also includes a non- alkaline active ingredient. The non-alkaline active ingredient is also compartmentalized to the thiamine containing layer.

[0014] In still yet an even further embodiment, the formulation also includes an acidic active ingredient. The acidic ingredient is also compartmentalized to the thiamine containing layer.

[0015] In still yet an even further embodiment, the acidic active ingredient is phenylephrine HCI.

[0016] In still yet an even further embodiment, the alkaline ingredient is also an active ingredient.

[0017] In still yet an even further embodiment, the alkaline ingredient is chlorpheniramine maleate.

[0018] In still yet an even further embodiment, the thiamine is thiamine hydrochloride. [0019] In an embodiment, a formulation for mitigating thiamine instability includes a multilayer tablet that includes thiamine, an acidic buffering agent and two or more active ingredients. The two or more active ingredients includes a non-alkaline active ingredient and an alkaline active ingredient. The thiamine, an acidic buffering agent, and the non- alkaline active ingredient are compartmentalized to a first layer and the alkaline active ingredient is compartmentalized to a second layer.

[0020] In another embodiment, the thiamine is thiamine hydrochloride. The acidic buffering agent is citric acid monohydrate. The non-alkaline active ingredient is phenylephrine hydrochloride. The alkaline active ingredient is chlorpheniramine maleate.

[0021] In yet another embodiment, the formulation also includes paracetamol.

[0022] In a further embodiment, the thiamine hydrochloride is 0.44% of the total weight of the tablet. The citric acid monohydrate is 0.90% of the total weight of the tablet. The phenylephrine hydrochloride is 1.0% of the total weight of the tablet.

[0023] In still yet another embodiment, the thiamine containing layer is 50% of the total weight of the tablet.

[0024] In an even further embodiment, the thiamine containing layer is 25% of the total weight of the tablet.

[0025] In still yet an even further embodiment, the thiamine containing layer is 10% of the total weight of the tablet.

BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The description will be more fully understood with reference to the following figures, which are presented as exemplary embodiments of the invention and should not be construed as a complete recitation of the scope of the invention, wherein:

[0027] Fig. 1 illustrates a schematic of an apparatus for forming pharmaceutical formulations in accordance with embodiments.

[0028] Fig. 2 provides a data graph of thiamine stability in various formulations over 6 months with different local citric acid concentrations in chlorpheniramine layer of the bilayer tablets at 40°C/75%RH conditions, generated in accordance with embodiments. [0029] Fig. 3 provides a data graph of thiamine stability in various formulations over 6 months with different local citric acid concentrations in phenylephrine layer of the bilayer tablets at 40°C/75%RH conditions, generated in accordance with embodiments.

DETAILED DESCRIPTION OF THE INVENTION

[0030] Turning now to the disclosure and examples, pharmaceutical formulations having thiamine and methods of their formation are provided that mitigate thiamine instability. In various embodiments, formulations incorporate various strategies to prevent thiamine instability while maintaining the same overall formulation composition. In several embodiments, thiamine formulations further incorporate an increased local concentration of an acidic buffer reagent (e.g., citric acid) to control the local pH around thiamine, and thus enhance the stability of thiamine. In some such embodiments, the local concentration of an acidic buffer reagent is increased in the regions having thiamine by compartmentalizing thiamine and the acidic buffer reagent to a particular layer in a multilayer tablet. In many embodiments, a layer having an acidic buffer reagent and thiamine are reduced in weight and/or layer volume compared to tablet total weight and/or volume such that the local concentration of each the acidic buffer reagent and thiamine are relatively increased, and thus increasing the local concentration of the acidic buffer reagent surrounding thiamine.

[0031] In several embodiments, thiamine formulations incorporate at least one active ingredient. A number of embodiments of formulations have thiamine and one or more active ingredients in two separate layers of a multilayer tablet. In some of such embodiments, thiamine is kept in a layer separate from alkali ingredients. In many embodiments, formulations incorporate both alkali (e.g., chlorpheniramine maleate) and non-alkali ingredients, and each are provided with in separate layers. In some of these embodiments, formulations further group thiamine, an acidic buffer reagent, and at least one non-alkali ingredient into a single layer of the formulation. Thiamine Stabilization by Acidic Pharmaceutical Ingredients

[0032] Many pharmaceutical compositions incorporate thiamine; however, thiamine is unstable in alkali conditions. It is known that acidifying the environment of thiamine improves its stability. Although acidic ingredients such as citric acid has been frequently added to such formulations, instability of thiamine is still observed. Accordingly, embodiments of pharmaceutical formulations are provided to address the stability of thiamine.

[0033] Several embodiments are directed to multilayer formulations that separate various ingredients, especially labile thiamine from alkali ingredients. Provided in Fig. 1 is a bilayer tablet compression machine to fabricate bilayer tablets. Although Fig. 1 depicts bilayer tablets, it should be understood that embodiments of formulations as described herein include multilayer tablets beyond two layers, as appropriate to the composition to be constructed. Furthermore, although stacked layers are shown in Fig. 1 , it should be understood that layers of a multilayer tablet do not need to be stacked. It should be further understood that the term“layer” is to connote any three dimensional region within a tablet as defined by at least one constituent.

[0034] In various embodiments, a multilayer pharmaceutical formulation is provided such that thiamine is placed into at least one layer, and ingredients identified as alkali are disposed in separate layers to minimize their contact with thiamine. In some such embodiments, thiamine and non-alkali ingredients are disposed within the same layer of the multilayer formulation.

[0035] In several embodiments, multilayer formulations include thiamine which is placed in the same layer with an acidic active pharmaceutical ingredients. For example, embodiments of formulations have thiamine in the same layer with phenylephrine hydrochloride, which is acidic.

[0036] In a number of embodiments, multilayer formulations are provided that include both thiamine and ingredients identified as alkali. In such embodiments, thiamine and alkali ingredients are buffered with an acidic agent to prevent the degradation of thiamine when disposed within the same layer of the multilayer formulation. In some such embodiments, an acidic buffered agent is citric acid, acetic acid, carbonic acid, bicarbonate, phosphoric acid, monopotassium phosphate, ascorbic acid, tartaric acid, fumaric acid, hydrochloric acid, benzoic acid, or similar pharmaceutically acceptable pH modifier.

[0037] In many embodiments, an acidic buffering agent and thiamine are added to a layer excluding alkali ingredients. Compartmentalizing an acidic buffering agent and thiamine to a single layer of a multilayer formulation increases the local concentration of the acidic buffering agent around thiamine and thus improves its stability. In some such embodiments, an acidic buffering agent is citric acid monohydrate. In many embodiments, citric acid monohydrate total concentration in the composition is constant (e.g., 0.9%) but can be compartmentalized to a layer along with thiamine to further increase the local concentration. For example, compartmentalizing thiamine and an acidic reagent to a layer that is half of a tablet, the local concentration of the acidic buffering agent surrounding thiamine is increased 2-fold. Accordingly, a number of local concentrations are relative to the layer size. In numerous embodiments, thiamine and an acidic buffering agent are compartmentalized to a layer having a particular layer size that is a percentage of the total tablet size to increase the local concentration of the acidic buffering agent surrounding thiamine by a fold-amount, as detailed in Table 1.

[0038] Many embodiments of pharmaceutical formulations may stabilize thiamine in the formulation by controlling one or both the weight and/or volume of a layer having an acidic buffer agent with thiamine to increase the local acidic buffer agent concentration without also requiring a concomitant change in the overall composition of the registered pharmaceutical formulation. Thiamine Stabilization by Separating it from Alkaline Pharmaceutical Ingredients

[0039] Numerous embodiments of the invention incorporate further pharmaceutical ingredients along with thiamine in the same formulation. In some of these embodiments, a pharmaceutical ingredient is an alkali (e.g. chlorpheniramine maleate), which potentially can increase thiamine instability. As described herein, thiamine stability can be improved with formulations having an alkali ingredient by compartmentalization and/or incorporating an acidic buffering reagent.

[0040] A number of alkali pharmaceutical ingredients are known in the art. Alkali pharmaceutical ingredients may include but not limit to caffeine, chlorpheniramine maleate, cinnarizine, dextromethorphan, famotidine, guaifenesin, loperamide, noscapine and paracetamol. Structures of several alkali pharmaceutical ingredients are shown below:

Caffeine Chlorpheniramine Dextromethorphan

Famotidine Guaifenesin

Loperamide Paracetamol

[0041] It should be understood that the listed alkaline pharmaceutical ingredients are not exhaustive and many more are known or described in the art that would also fall within various embodiments of the invention.

Thiamine Stabilization by Incorporating Thiamine with Acidic Pharmaceutical Ingredients in the Same Layer

[0042] Numerous embodiments of the invention incorporate further pharmaceutical ingredients along with thiamine in the same formulation. In some of these embodiments, a pharmaceutical ingredient is acidic (e.g. phenylephrine HCI), which potentially can increase thiamine stability. As described herein, thiamine stability can be improved with formulations having an acidic ingredient by incorporating thiamine with the acidic ingredient in the same layer.

[0043] A number of acidic pharmaceutical ingredients are known in the art. Acidic active pharmaceutical ingredients may include but not limit to ibuprofen, isopropylphenazone, loratadine, pheniramine maleate and triprolidine hydrochloride.

[0044] It should be understood that the listed acidic pharmaceutical ingredients are not exhaustive and many more are known or described in the art that would also fall within various embodiments of the invention.

Formulations

[0045] Provided herein are various embodiments of pharmaceutical compositions which incorporate thiamine, one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. In certain embodiments requiring compartmentalization of at least one component may be limited to a manufacturing process that yields compartmentalized layers, such as a multilayer tablet. Pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast- , targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, 21 st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Modified-Release Drug Delivery Technology, Rathbone et al, Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc., New York, NY, 2002; Vol. 126).

[0046] The terms "active ingredient," "active compound," and "active substance" refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder.

[0047] The compounds disclosed herein can exist as therapeutically acceptable salts. The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with a suitable acid or base. Therapeutically acceptable salts include acidic and basic salts. For a more complete discussion of the preparation and selection of salts, refer to "Handbook of Pharmaceutical Salts, Properties, and Use," Stah and Wermuth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) and Berge et al, J. Pharm. Sci. 1977, 66, 1 -19. [0048] Several embodiments incorporate at least one active ingredient along with thiamine. In some embodiments, an active ingredient is incorporated in a layer having thiamine, especially those that are non-alkaline. In many embodiments, an active ingredient is incorporated into a layer exclusive of thiamine. In some such embodiments, an active ingredient is an alkali and excluded from the layer having thiamine to mitigate thiamine instability.

[0049] Practically any active ingredient can be used in the methods and formulations of the present invention, although those exhibiting alkaline properties may be compartmentalized and/or neutralized in some fashion to prevent thiamine instability. In many embodiments, an active ingredient is selected from the group consisting of guaifenesin, noscapine, bromhexine, diphenhydramine, dextromethorphan, paracetamol, ibuprofen, ketoprofen, loratadine, cetirizine, norepinephrine, phenylephrine, caffeine, chlorpheniramine maleate and acetylsalicylic acid, and combinations thereof, wherein any of said active ingredients can be present as a pharmaceutically acceptable salt. In several embodiments, an active ingredient is selected from the group consisting of non- steroidal medications, anti-inflammatory medications, allergy medications, analgesics, antacids, anticholinergics, antidiarrheals, antiemetics, antiflatulents, antihistamines, antirheumatics, antitussives, bronchodilators, decongestants, expectorants, laxatives, sleep aids, sedatives, smoking deterrents, stimulants and stomach acidifiers, and combinations thereof, wherein any of the active ingredients can be presented as its pharmaceutically acceptable salt.

[0050] Numerous coating agents can be used in accordance with various embodiments of the invention. In some embodiments, the coating agent is one which acts as a coating agent in conventional delayed release oral formulations, including polymers for enteric coating. Examples include hypromellose phthalate (hydroxypropyl methyl cellulose phthalate; HPMCP); hydroxypropyl cellulose (HPC; such as KLUCEL®); ethyl cellulose (such as ETHOCEL®); and methacrylic acid and methyl methacrylate (MAA/MMA; such as EUDRAGIT®).

[0051] Various embodiments of formulations also include at least one disintegrating agent, as well as diluent. In some embodiments, a disintegrating agent is a super disintegrant agent. One example of a diluent is a bulking agent such as a polyalcohol. In many embodiments, bulking agents and disintegrants are combined, such as, for example, PEARLITOL FLASH®, which is a ready to use mixture of mannitol and maize starch (mannitol/maize starch). In accordance with a number of embodiments, any polyalcohol bulking agent can be used when coupled with a disintegrant or a super disintegrant agent. Additional disintegrating agents include, but are not limited to, agar, calcium carbonate, maize starch, potato starch, tapioca starch, alginic acid, alginates, certain silicates, and sodium carbonate. Suitable super disintegrating agents include, but are not limited to crospovidone, croscarmellose sodium, AMBERLITE (Rohm and Haas, Philadelphia, Pa.), and sodium starch glycolate.

[0052] In certain embodiments, diluents are selected from the group consisting of mannitol powder, spray dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugars, silicified microcrystalline cellulose, and calcium carbonate.

[0053] In some embodiments, diluents are selected from the group consisting of direct compressed materials, for example, Flowlac@, Tablettose@, Cellactose@, in order to compromise a direct compression formulation.

[0054] Several embodiments of a formulation further utilize other components and excipients. For example, sweeteners, flavors, buffering agents, and flavor enhancers to make the dosage form more palatable. Sweeteners include, but are not limited to, fructose, sucrose, glucose, maltose, mannitol, mannose, galactose, lactose, sorbitol, sucralose, saccharin, aspartame, acesulfame K, and neotame. Common flavoring agents and flavor enhancers that may be included in the formulation of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.

[0055] Multiple embodiments of a formulation also include a surfactant. In certain embodiments, surfactants are selected from the group consisting of Tween 80, sodium lauryl sulfate, and docusate sodium.

[0056] Many embodiments of a formulation further utilize a binder. In certain embodiments, binders are selected from the group consisting of sugars, for example, sucrose, liquid glucose; or the group consisting of natural binders, for example, acacia, tragacanth, gelatin, starch paste, pregelatinized starch, alginic acid, cellulose; or the group consisting of synthetic/semisynthetic polymer, for example, methyl cellulose, ethyl cellulose, povidone (PVP), copovidone (PVP/VA), crospovidone, microcrystalline cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, polyethylene glycol (PEG).

[0057] Various embodiments of a formulation also include a lubricant. In certain embodiments, lubricants are selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

[0058] Modes of administration, in accordance with multiple embodiments, include, but are not limited to, oral or transmucosal (e.g., sublingual, or buccal). The actual amount of drug needed will depend on factors such as the size, age and severity of disease in the afflicted individual. The actual amount of drug needed will also depend on the effective concentration ranges of the various active ingredients.

[0059] A number of embodiments of formulations include those suitable for oral administration. Formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically salt, prodrug, or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients.

[0060] Embodiments of formulations disclosed herein suitable for oral administration may be presented as discrete units such as tablets each containing a predetermined amount of the active ingredient.

[0061] Tablets, in a number of embodiments, may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents (e.g., Fig. 1 ). [0062] Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. Cores of sugar-coated tablets are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or sugar coatings for identification or to characterize different combinations of active compound doses.

[0063] In some embodiments, thiamine containing formulations are administered in a therapeutically effective amount as part of a course of treatment. As used in this context, to "treat" means to ameliorate at least one symptom of a disorder to be treated or to provide a beneficial physiological effect. For example, one such amelioration of a symptom could be reduction of rhinitis-like symptoms.

[0064] A therapeutically effective amount can be an amount sufficient to prevent, reduce, ameliorate or eliminate the symptoms of diseases or pathological conditions susceptible to such treatment, such as, for example, common cold, influenza, or allergic rhinitis.

[0065] Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LDso (the dose lethal to 50% of the population) and the EDso (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to non-neoplastic cells and, thereby, reduce side effects.

[0066] Data obtained from cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. If the medicament is provided systemically, the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration or within the local environment to be treated in a range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of neoplastic growth) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by liquid chromatography coupled to mass spectrometry.

[0067] An "effective amount" is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered one from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. For example, several divided doses may be administered daily, one dose, or cyclic administration of the compounds to achieve the desired therapeutic result.

[0068] Preservatives and other additives, like antimicrobial, antioxidant, chelating agents, and inert gases, can also be present. (See generally, Remington's Pharmaceutical Sciences, cited supra.) EXEMPLARY EMBODIMENTS

[0069] The embodiments of the invention will be better understood with the several examples provided within. Many exemplary formulations having thiamine are provided. Also provided are data detailing the stability of thiamine over the course of time.

[0070] Provided in Table 2 is a summary of experimental trials and detailed in Table 3 is the complete formulation used in these trials. In these embodiments, chlorpheniramine maleate is an alkaline constituent that may increase the pH of a formulation causing thiamine instability. In addition, citric acid is provided as an acidic buffering agent to mitigate thiamine instability. Phenylephrine hydrochloride, paracetamol, and chlorpheniramine maleate are common active ingredients provided in a treatment for common cold, allergic rhinitis, or similar condition.

[0071] In some of the exemplary formulations, thiamine is compartmentalized in a layer with some other various constituents, as described here below:

[0072] Utilizing the exemplary formulations, embodiments may be provided wherein the stability of thiamine in the formulation may be enhanced without altering the overall registered formulation of the pharmaceutical preparations. In some such embodiments, the modification can include:

• Providing a multilayer formulation;

• Separating thiamine from ingredients having an alkali nature;

• For example, separating the thiamine containing layer from the chlorpheniramine maleate component.

• For example, incorporating into the thiamine containing layer the phenylephrine hydrochloride component;

• Including within the thiamine containing layer a concentration of citric acid;

• Increasing the local concentration of citric acid in the thiamine layer by reducing the weight/thickness contribution of the layer in the multilayer formulation (e.g., from 50% of the formulation to 25% or appropriate other ratios);

• The above modification may be applied to varied overall formulation compositions.

[0073] Provided in Table 4, and Figs. 2 and 3 are stability results of thiamine within the various formulations (data normalized) as described in trials 1 through 7. Each formulation was tested for accelerated stability storage at 40°C with 75% relative humidity (RH) for up to 6 months. Thiamine levels were determined by HPLC, and the relative thiamine levels, as compared to thiamine concentration in the prepared formula, were charted and plotted. [0074] As can be determined by Table 4 and Figs. 2 and 3, concentrating the citric acid from x1 to x2 in chlorpheniramine layer showed significant improvement in thiamine stability at 40°C/ 75%RH accelerated conditions for 6 months.

[0075] Further increasing the local citric acid concentration from x2 to x4 in chlorpheniramine layer did not improve the thiamine stability further. The citric acid concentration appears to reach a plateau between x2 and x4 for optimum stability of thiamine.

[0076] As can be determined by Table 4 and Figs. 2 and 3, concentrating the citric acid from x1 to x2 in phenylephrine layer showed significant improvement in thiamine stability at 40°C/ 75%RH accelerated conditions for 6 months.

[0077] Further increasing the local citric acid concentration from x2 to x4 in phenylephrine layer did not improve the thiamine stability further. The citric acid concentration appears to reach a plateau between x2 and x4 for optimum stability of thiamine.

[0078] Thiamine HCI was more stable when incorporated into the phenylephrine HCI layer compared to when it was incorporated into the chlorpheniramine maleate layer at 40°C/ 75%RH accelerated conditions. Acidic environment appeared to favor the stability of thiamine HCI.

DOCTRINE OF EQUIVALENTS

[0079] In particular, as can be inferred from the above discussion, the above- mentioned concepts can be implemented in a variety of arrangements in accordance with embodiments of the invention. Accordingly, although the present invention has been described in certain specific aspects, many additional modifications and variations would be apparent to those skilled in the art. It is therefore to be understood that the present invention may be practiced otherwise than specifically described. Thus, embodiments of the present invention should be considered in all respects as illustrative and not restrictive.

Claims

WHAT IS CLAIMED IS:

1. A formulation for mitigating thiamine instability comprising:

a multilayer tablet comprising thiamine, an acidic buffering agent and an alkaline ingredient, wherein the thiamine and the alkaline ingredient are compartmentalized in separate layers.

2. The formulation of claim 1 , wherein the acidic buffering agent is compartmentalized to the thiamine containing layer.

3. The formulation of claim 2, wherein the acidic buffering agent is selected from the group consisting of: citric acid, acetic acid, ascorbic acid, tartaric acid, fumaric acid, carbonic acid, bicarbonate, phosphoric acid, hydrochloric acid and monopotassium phosphate.

4. The formulation of claim 2, wherein the acidic buffering agent is citric acid monohydrate.

5. The formulation of claim 2, wherein the relative size of the thiamine containing layer as compared to the total tablet size is selected from the group consisting of: 100%, 75%, 66%, 50%, 33%, 25%, 20%, 15%, and 10%.

6. The formulation of claim 5, wherein the relative size of the thiamine containing layer as compared to the total tablet size is 50%.

7. The formulation of claim 5, wherein the relative size of the thiamine containing layer as compared to the total tablet size is 25%.

8. The formulation of claim 5, wherein compartmentalization of the acidic buffering agent increases its local concentration within the thiamine containing layer while the total concentration of the acidic buffering agent for the whole multilayer tablet remains constant.

9. The formulation of claim 2 further comprising a non-alkaline active ingredient, wherein the non-alkaline active ingredient is also compartmentalized to the thiamine containing layer.

10. The formulation of claim 2 further comprising an acidic active ingredient, wherein the acidic ingredient is also compartmentalized to the thiamine containing layer.

1 1. The formulation of claim 10, wherein the acidic active ingredient is phenylephrine HCI.

12. The formulation of claim 1 , wherein the alkaline ingredient is also an active ingredient.

13. The formulation of claim 12, wherein the alkaline ingredient is chlorpheniramine maleate.

14. The formulation of claim 1 , wherein the thiamine is thiamine hydrochloride.

15. A formulation for mitigating thiamine instability, comprising:

a multilayer tablet comprising thiamine, an acidic buffering agent and two or more active ingredients, wherein the two or more active ingredients includes a non-alkaline active ingredient and an alkaline active ingredient, and wherein the thiamine, an acidic buffering agent, and the non-alkaline active ingredient are compartmentalized to a first layer and the alkaline active ingredient is compartmentalized to a second layer.

16. The formulation of claim 15, wherein the thiamine is thiamine hydrochloride, the acidic buffering agent is citric acid monohydrate, the non-alkaline active ingredient is phenylephrine HCI, and the alkaline active ingredient is chlorpheniramine maleate.

17. The formulation of claim 16 further comprising paracetamol.

18. The formulation of claim 16, wherein the thiamine hydrochloride is 0.44% of the total weight of the tablet, the citric acid monohydrate is 0.90% of the total weight of the tablet, and phenylephrine hydrochloride is 1.0% of the total weight of the tablet.

19. The formulation of claim 18, wherein the thiamine containing layer is 50% of the total weight of the tablet.

20. The formulation of claim 18, wherein the thiamine containing layer is 25% of the total weight of the tablet.

21. The formulation of claim 18, wherein the thiamine containing layer is 10% of the total weight of the tablet.