GR1010840B - Compositions of orally dispersible tablets with probiotics, zinc and viatamin c - Google Patents

Abstract

The present invention describes a novel pharmaceutical composition comprising a sporogenous probiotic microorganism and other nutritionally active components such as zinc and vitamin C coming in the form of an orally dispersible tablet and in effective amounts for enhanced absorption through mucous membranes (mouth). The aim of the invention is to improve any condition related to zinc and vitamin C deficiency as well as the general gastrointestinal and respiratory disorders.

Description

[0001] Orodispersible tablet compositions with probiotics, zinc and vitamin C

[0003] DESCRIPTION

[0005] Object of the invention

[0007] The present invention describes a novel pharmaceutical composition comprising a spore-forming probiotic microorganism and other nutritionally active ingredients such as zinc and vitamin C in tablet form, orally administered, in effective amounts for enhanced absorption through mucous membranes such as the mouth, for the purpose of improving any condition related to zinc and vitamin C deficiency and general gastrointestinal and respiratory disorders in the patient.

[0009] Existing/pre-existing knowledge

[0011] Introduction

[0013] The oral route of administration for most therapeutic ingredients in order to achieve their systemic action, compared to many other routes, represents the preferred mode of administration due to its several advantages and high patient compliance.

[0015] Tablets and capsules are the most familiar dosage forms. However, a significant disadvantage of such dosage forms is "Dysphagia" or difficulty in swallowing capsules, resulting in medications not being taken as prescribed. The incidence of dysphagia in the general population is estimated to be around 20% and is estimated to affect up to 50% to 66% of people over 60 years of age.

[0016] The European Pharmacopoeia uses the term orodispersible tablets. This can be defined as uncoated tablets intended to be placed in the mouth where they are easily dispersed before being swallowed.

[0018] When placed in the mouth, these dosage forms dissolve immediately to release the drug, which dissolves or disperses in the saliva. From there, the drug can be absorbed from the pharynx and esophagus or from other parts of the gastrointestinal tract as the saliva moves down. In such cases, the bioavailability is significantly greater than that observed from the conventional tablet dosage form.

[0020] In recent years, formulations for rapidly dissolving drugs have been developed to overcome the problems associated with swallowing difficulties. When these tablets are placed in the oral cavity, saliva quickly penetrates the pores to cause rapid disintegration of the tablet.

[0021] Background of the invention

[0023] The term "probiotic microorganism" is well understood by those skilled in the art to which this invention relates. Probiotics are microorganisms, which in tablet formulations are in lyophilized form and are also alive, which have a beneficial effect on health when ingested. Probiotic microorganisms can be lactic acid-producing bacteria, e.g. lactobacilli, bifidobacterium or bacilli. Bacillus probiotic microorganisms include, but are not limited to: Bacillus coagulans. Bacillus cereus, Bacillus clausii. Bacillus licheniformis, Bacillus polyfermenticus, Bacillus subtilis.

[0025] Bacillus coagulans is a spore-forming lactic acid producing bacteria. This strain can produce coagulin, a bacteriocin, which has antimicrobial activity against a broad spectrum of enteric microbes. In addition, this strain has been generally recognized as safe (GRAS) by the FDA. Coagulin produced by B. coagulans is plasmid-linked, heat-stable, and protease-sensitive, and exhibits both bactericidal and bacteriolytic activity. In humans, B. coagulans reduces blood lipid concentrations. Reductions in total cholesterol and LDL have been reported. B. coagulans reduces upper respiratory and gastrointestinal symptoms. B. coagulans is used to treat diarrhea and prevent Candida infections. Taking B. coagulans and other probiotic supplements while taking antibiotic medications is sometimes recommended to protect against gastrointestinal side effects and fungal infections.

[0027] Zinc. Zinc deficiency is when the body does not have enough of the trace element zinc. Zinc is important for the immune system, wound healing, and normal growth and development during pregnancy, childhood, and adolescence. Zinc deficiency can lead to skin changes that initially resemble eczema. There may be cracks and a sheen to the skin, often found around the mouth, diaper area, and hands. The rash does not improve with moisturizers or steroid creams or lotions.

[0029] People with zinc deficiency may also experience hair loss, nail changes, diarrhea, more infections, irritability, loss of appetite, impotence, eye problems, weight loss, wounds that take a long time to heal, and loss of taste and smell. Zinc deficiency can slow a child's growth and delay sexual maturity.

[0031] Some people may not get their daily zinc needs from their diet. Protein helps the body absorb zinc, so vegetarians and vegans, as well as people who follow long-term restricted diets, may be at greater risk. Zinc deficiency can occur in people who have problems absorbing nutrients, for example, in the elderly and in people who have certain bowel conditions. Some medications can also increase the loss of zinc through the urine.

[0033] Zinc deficiency is widespread in children in developing countries and occurs in most of Latin America, Africa, the Middle East and South Asia. Zinc has been shown to play critical roles in metalloenzymes, polyribosomes, the cell membrane and cellular function, leading to the belief that it also plays a central role in cellular development and immune function. Although the theoretical basis for the potential role of zinc has been postulated for some time, convincing evidence for its importance in children's health has only recently emerged from randomized controlled trials of zinc supplementation.

[0035] Numerous studies have now shown that zinc supplementation (10-20 mg per day until diarrhea stops) significantly reduces the severity and duration of diarrhea in children under 5 years of age. Additional studies have shown that short-term zinc supplementation (10-20 mg per day for 10 to 14 days) reduces the incidence of diarrhea for 2 to 3 months.

[0037] Based on these studies, it is now recommended that zinc (10-20 mg/day) be administered for 10 to 14 days to all children with diarrhea.

[0039] Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods and is also available as a dietary supplement. Because humans lack the enzymes to synthesize vitamin C endogenously, it is necessary to obtain this nutrient through dietary sources. Vitamin C is a critical component of the biosynthesis of collagen, L-carnitine, and many neurotransmitters, and is involved in the metabolism of certain proteins. In addition, vitamin C is known to have anticancer effects by inhibiting the production of carcinogenic narrosamines in the acidic environment of the stomach, supported by the association between high vitamin C intake and low rates of stomach cancer. Vitamin C is absorbed into intestinal cells through several different mechanisms. The uptake of vitamin C is mediated either by active Na+-dependent transporters - transporting both the oxidized ascorbic acid (dehydroascorbic acid) and the reduced form (L-ascorbic acid) - or by glucose transporters only in the oxidized form. These absorption mechanisms in cell membranes regulate the concentration of vitamin C in tissues and plasma. Consumption of 2000 mg of Vitamin C per day is considered safe, but studies show that oral intake is reduced to 50% if it is above 1000 mg per day. The unabsorbed vitamin C molecules, before being excreted in the urine, benefit the body by reducing nitrosamine production, reducing the risk of stomach cancer, by increasing the intake of non-heme iron and improving the body's condition. As pharmacokinetic studies conclude that the relative bioavailability of vitamin C peaks at a dose of 200 mg, taking several smaller doses each day is preferable to a single large dose. Other studies have examined the effect of vitamin C tablet formulations on their relative bioavailability and have shown that slow-release formulations had the highest bioavailability.

[0041] The composition of vitamin C tablets also affects the relative bioavailability. Sodium ascorbate and calcium ascorbate are absorbed more rapidly and excreted more slowly, and have been shown to have superior anti-scorbutic activity compared to ascorbic acid, with a significant difference in bioavailability in humans. Calcium ascorbate in combination with calcium threonate reduces gastrointestinal symptoms in acid-sensitive individuals. The addition of calcium to vitamin C tablets reduces the side effects of taking vitamin C alone - the depletion of calcium stores in the body and chronic digestive difficulties in sensitive stomachs - as the calcium ions neutralize the acidic properties of ascorbic acid in the stomach, resulting in no significant decrease in pH. Additionally, calcium is known as an essential nutrient for proper health, serving as a building block for strong bones and teeth and improving the immune system.

[0043] Acerola (Malpighia emarginata DC.) is one of the richest natural sources of ascorbic acid and contains a variety of phytonutrients such as carotenoids, phenolics, anthocyanins and flavonoids. The fruit contains a large amount of ascorbic acid of the order of 1500-4500 mg/100 g, which is about 50-100 times higher than that of orange or lemon. Having a variety of phytonutrients, the fruit exhibits high antioxidant capacity. Therefore, this super fruit may have great functional importance.

[0045] Dog rose [Rosa canina L.) is a term used to refer to extracts of the rose plant of the Rosagenus, but almost always refers specifically to Rosa canina.

[0047] The fruits, and occasionally the seeds, are either ground into a powder or made into a tea and then used to treat rheumatic diseases such as osteoarthritis and rheumatoid arthritis. It improves joint health by reducing pain and stiffness.

[0049] Preliminary evidence also suggests that rosehip may offer benefits to people with diabetes, as well as people with high blood pressure and cholesterol.

[0050] Rosehip can also reduce chemotaxis, the transport of immune cells into tissue. This serves as both an anti-inflammatory and immunosuppressive mechanism.

[0052] Roses contain bioflavonoids that occur naturally with vitamin C. Bioflavonoids help enhance absorption and bioavailability, ensuring you get all the benefits of vitamin C.

[0053] Modes of administration

[0055] Tablets, capsules, syrups and powders have different types of delivery mechanisms for the active substances. For the desired effect, the active substance must be delivered to its site of action at such a rate and concentration that the maximum effect and the minimum negative effect are achieved.

[0057] Most substances penetrate the barrier by molecular diffusion or by pore diffusion, that is, through the pores. In pore diffusion, the drug is released at a controlled rate by the crystal size, molecular size, pore size, and pore structure.

[0059] In passive permeation, substances pass from high concentration to low.

[0060] In active permeation, energy is required to move a substance from an area of low to high concentration through one or more transport mechanisms. It requires energy or a carrier such as an enzyme or protein.

[0062] The best dissolution time for an orodispersible tablet is considered to be less than one minute. The disintegration times for most commercially available tablets range from 5 to 30 seconds when the tablets are prepared by direct compression. Of all these methods, direct compression is preferred due to its convenience, rapidity and cost-effectiveness. Orodispersible tablets are created by adding superdisintegrants such as cross-linked cellulose derivatives, carboxymethylcellulose, sodium starch glycolate, polyvinylpyrrolidone, which cause disintegration when in contact with water or sebaceous secretions. The bioavailability of drugs can be increased due to oral and pregastric absorption, reducing first-pass metabolism in the gastrointestinal tract.

[0064] There are some requirements for rapidly disintegrating tablets referred to as:

[0066] The tablet should disintegrate and disperse in the oral cavity without water intake.

[0067] Contain a high amount of active substance.

[0068] It should be compatible with the taste masking ingredients and excipients and have an optimal sensory effect.

[0069] Leave little to no residue after administration.

[0070] It should have the optimal ability to remain intact in the synthesis processes.

[0071] It should be stable over a range of temperature and humidity.

[0072] It should be adaptable to existing processing and packaging machinery.

[0073] • It should be manufactured at low cost.

[0075] The present invention shows that it is possible to administer probiotic microorganisms in an orally disintegrating tablet together with zinc, vitamin C and plant extracts, with excellent product stability. To date, no pharmaceutical composition is known to include a combination of Zinc and Vitamin C with probiotic microorganisms in an orally disintegrating tablet, which allows for effective synergy and enhanced absorption through mucous membranes such as the mouth to improve any condition associated with zinc and vitamin C deficiency and general gastrointestinal and respiratory disorders in the patient.

[0076] Summary of the invention

[0078] The inventor has discovered a pharmaceutical composition and a pharmaceutical form for the administration of vitamin C, zinc and spore-forming probiotic microorganisms to humans with vitamin C, zinc and probiotic deficiencies.

[0080] An advantage of the present invention is that it provides a pharmaceutical composition comprising an effective amount of a mixture of Vitamin C, Zinc and Bacillus coagulans and a pharmaceutically acceptable carrier in a single tablet zone.

[0082] An advantage of the present invention is that it provides a pharmaceutical composition wherein said composition is in the form of an orodispersible tablet.

[0084] A further advantage is that the present invention provides a method of treating or ameliorating a disease associated with vitamin C and zinc deficiency and a lack of probiotics in the gut microbiome, comprising administering to a subject suffering from or suspected of suffering from said disease, an effective amount of the pharmaceutical composition formulation.

[0086] The present invention provides a method of treating or ameliorating a disease or syndrome in a subject, comprising administering to said subject an effective amount of the pharmaceutical composition of the formulation, wherein said disease or syndrome consists of diarrhea, antibiotic-associated diarrhea, bleeding gums, joint and muscle pain, more infections, feeling irritable, impotence, respiratory tract infections, eye problems, hair loss, nail changes, loss of appetite, weight loss, wounds that take a long time to heal, loss of taste and smell.

[0088] According to the invention, vitamins C, zinc and probiotics are infused into a carrier matrix of orodispersible tablets for patient-friendly, self-administration of effective amounts of vitamin C, zinc and probiotics. The vitamins C and zinc in the orodispersible tablet composition are released in the mouth and are initially absorbed directly through the oral mucosa into the bloodstream before undergoing digestion and degradation in the liver, providing maximum bioavailability compared to conventional dosage forms. The invention thus minimizes patient discomfort and reduces the difficulty and time requirements imposed on medical personnel.

[0090] The composition of the present invention may be prepared in a specific dosage and form as described herein.

[0092] Description of the invention

[0094] To achieve the desired therapeutic effect, different amounts of spore-forming probiotic microorganisms Bacillus coagulans from 1 billion to 30 billion, vitamin C as sodium ascorbate and calcium ascorbate from 80mg to 1000mg, zinc as zinc picolinate from 1mg to 25mg, Calcium threonate from 5mg to 100mg, Acerola extract from 1mg to 100mg and Rose extract from 1mg to 100mg are included in the formulation of the present invention.

[0096] The present invention relates to the formulation of spore-forming probiotics in the form of orally dispersible tablets. Probiotics are normally conventionally formulated with other nutritionally active materials such as vitamins, minerals, carbohydrates, plant extracts, trace elements and fats. While many probiotics are quite stable when stored alone in lyophilized form, tablet formulations in which probiotics are mixed with active ingredients of the above species are extremely unstable. Even after short and good storage, the recovery of viable microorganisms upon rehydration of such mixed formulations will be extremely poor.

[0098] Since microorganisms require water to multiply, water activity rather than water content is a better measure of the free water required by microbial cells for metabolic activity.

[0099] Mathematically, water activity (Aw) is the ratio of the vapor pressure of water in a product (P) to the vapor pressure of pure water (Po) at the same temperature (Aw = P/Po). Water activity ranges from 1.00 for pure water to 0.00 for a dry material. Tablets are the most common pharmaceutical dosage form, which typically have a water activity of 0.3-0.4 if stored in moisture-proof packaging. The growth of microorganisms within a pharmaceutical product can be controlled by the inherently low water activity.

[0101] So far we know that the tablet should be in multilayer form with the probiotics contained in a separate layer free from other nutritionally active materials, anhydrous to the extent that its water content is less than 0.1% (U.S. Pat. No. 6,254,886). Water is in fact free to move between the different layers of the tablet, this means that the carrier material for all tablet layers should be dry to the same extent. Where large amounts of other active ingredients are present, they should be intensively dried to a low and limited level. US 2007/0269515 reports that they managed to get good stability results for probiotics in a separate tablet zone, with a water content between 3% and 4% and a maximum water activity of 0.15.

[0103] The present invention discovers that the water content in a formulation of spore-forming probiotic tablets under stable storage conditions can be higher than 0.1% (U.S. Pat. No. 6,254,886) using only one, the same tablet zone where the spore-forming probiotic and other active ingredients are together, taking into account that the water activity is maintained below 0.2, and the water content of said tablet is up to 4% by weight.

[0105] The present invention now provides a tablet with a spore-forming probiotic comprising other nutritionally active ingredients, in a single zone, which water content is not greater than 4% by weight and the water activity of said tablet is not greater than 0.2.

[0107] The tablets according to the invention, particularly as explained below, may be stable on storage at temperature (up to 20°C) or more preferably at room temperature (up to 25°C) for several months, e.g. for up to one year or more preferably up to 24 months or more preferably 36 months. By "stable storage" is meant that after a period of storage, the number of viable probiotic microorganisms should not have decreased by more than a factor of a thousand, preferably not more than a hundred, preferably not more than 10 e.g. from 1X10<9>CFU* to 1x10<8>CFU, or less preferably 1x10<7>CFU or even less preferably 1X10<6>CFU. (*CFU-colony forming units

[0109] The present invention provides an orally disintegrating tablet comprising a probiotic microorganism and other nutritionally active ingredients in a single zone, comprising said probiotic microorganism in granules and preferably at least one other said active ingredient such as zinc, iron, selenium, magnesium, manganese, copper, chromium and other minerals and vitamin A, B, C, D, E and other vitamins, with the water activity not being greater than 0.2 and the water content of said tablet being up to 4% by weight.

[0111] It is known that the presence of other nutritionally valuable substances can be detrimental to the stability of probiotics when they are together in a tablet zone. Active ingredients that are generally detrimental should preferably be excluded from the tablet matrix. These include iron, zinc, copper, manganese, chromium, vitamin C, vitamin B6, pantothenic acid or its salts. Considering that the nutritional value of spore-forming probiotic microorganisms is characterized by higher stability than non-spore-based probiotics, the present invention demonstrates that such materials can coexist with spore-forming probiotics in the tablet matrix in the same phase with excellent stability.

[0112] In the present invention, we have found that the use of spore-forming probiotic microorganisms with certain active ingredients does not actually affect the stability of the product. Accordingly, it is preferred that the tablet matrix contains zinc and vitamin C. Preferably, the tablet matrix contains zinc from 1 to 25 mg, e.g. 5 to 20 mg, more preferably 10 to 15 mg, and from 40 to 2000 mg, e.g. 80 to 1000 mg, more preferably 200 to 500 mg of vitamin C per 1x10<9>CFU of microorganisms.

[0114] In the present invention we have demonstrated that the presence of a zinc salt and sodium ascorbate and calcium ascorbate together with the spore-forming microorganisms in a single zone of a tablet under stable storage conditions has good viability of the microorganisms despite the relatively high total moisture content. The mechanism responsible for this is currently uncertain. It is possible that zinc and calcium ascorbate exert a beneficial effect in one or more of several ways, including as a growth medium or as an antioxidant.

[0116] In order to achieve low water activity, the probiotic microorganism is preferably mixed with a non-hygroscopic carrier which serves to reduce the water activity in the tablet matrix mixture. The effect of such a material may be to remove part of the water content, so that it is no longer in the form of free water which can affect the probiotic microorganisms and therefore prevent the transport of active substances through the cell membranes of the probiotics. Such materials bind water at specific sites, so that it is no longer able to act as a solvent. These sites include the hydroxyl groups of polysaccharides and others where water can be held by hydrogen bonds, ion-dipole bonds or other strong interactions. Thus, preferred desiccants include at least one of carboxymethylcellulose, colloidal silicon dioxide, polyvinylpyrrolidone, starch, hydroxypropylcellulose, microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, gelatin, xylitol or sorbitol. The desiccant may be, in particular, a starch selected from corn, rice or potato starch, a polysaccharide or galactomannan such as pectin, agar, dextran, maltodextrin, carrageenan, tragacanth gum, acacia gum, guar gum, xanthan gum, alginic acid or so on alginic acid salt.

[0118] In order to achieve the reduction of oxygen which is beneficial for product stability, packaging materials create a barrier to oxygen and moisture, such as aluminum or high barrier polymers. This may include packaging the tablets in a moisture impermeable material, such as an Alu-Alu or Alu-PVDC blister pack.

[0120] The water content may be above 0.5% or above 1%, but below 6%, more preferably below 5%, or 4%.

[0121] Water activity is related to the tablet matrix, and after internal equilibration, this will be the water activity of the tablet as a whole. The water activity is preferably below 0.2, more preferably below 0.15, e.g.

[0122] 0.10.

[0124] The tablets may contain additional materials, such as plant extracts, for example extracts of Acerola, Rose, Echinacea, Elderberry, Bilberry and Cranberry.

[0125] Each tablet will contain from 10<6>CFU, preferably from 10<7>CFU to 10<12>CFU, e.g. from 10<8>CFU to 10<10>CFU, of viable microorganisms.

[0127] The advantages of orodispersible tablets are:

[0129] It can be easily administered to patients with difficulty swallowing such as the elderly, stroke victims and pediatric patients. This increases compliance in bedridden patients, as well as in people who travel and have less access to water.

[0131] Active ingredients with a good mouthfeel may help to enhance psychological adherence to medication.

[0132] Ease of administration to both young and elderly patients.

[0133] Faster and higher absorption of active substances from pregastric parts of the gastrointestinal tract (GIT) improving bioavailability and efficacy.

[0134] Cost-effective as a minimum number of components are required.

[0135] Improved safety by preventing choking or obstruction as in the case of the conventional dosage form upon ingestion.

[0137] Preferred methods for producing tablets include standard tableting methods. As we have found that excessive tableting pressure can reduce the viability of microorganisms, we prefer that the compression pressure for the probiotic layer does not exceed 100N.

[0139] Tablets may be designed to be chewed or swallowed. When the tablets disintegrate during consumption, either in the mouth or in the stomach, microorganisms are exposed to the materials of which they are composed. Since spore-forming probiotics require several hours to be active in the aquatic environment, there is no possibility that the components released by the disintegration of the tablet will endanger spore-forming microorganisms.

[0141] The following examples illustrate preferred embodiments according to the present invention without limiting the scope or spirit of the invention. Example 1

[0143] According to one embodiment of the present invention, the process for preparing orodispersible tablets comprises the following steps:

[0145] Mixing active ingredients zinc picolinate, calcium ascorbate, sodium ascorbate, acerola extract, rose extract, calcium threonate with sodium carboxymethylcellulose and xylitol in a free-fall blender for up to 10 minutes, passed through a 0.8 mm mesh screen.

[0146] Mixing lyophilized Bacillus coagulans powder with the previously prepared mixture in a free-fall blender, for 10 minutes.

[0147] Mix PVP, sucralose, acesulfame K, steviol glycosides, beta-carotene and flavor powder with the previously prepared mixture in a free-fall blender, for 10 minutes.

[0148] Lubricate the mixture with magnesium stearate by mixing for 1 minute, passed through a sieve with a mesh size of 0.8 mm.

[0149] Compress the bulk mixture into tablets at 50N to 90N.

[0151] Example 2

[0153] Pharmaceutical form: dispersible tablet

[0155] The composition of the active substances per tablet:

[0157] Vitamin C from 80mg to 1000mg as calcium ascorbate, from 80 mg to 1000mg

[0158] as sodium ascorbate, from 80 mg to 1000mg

[0159] Zinc (as picolinate, gluconate, sulfate, etc.) from 1mg to 25mg Calcium threonate from 5mg to 100mg

[0161] Acerola extract from 1mg to 100mg (Malpighia glabra L.) standardized with

[0162] ascorbic acid minimum 17%

[0164] Rosehip extract from 1mg to 100mg (Rosa canina L.) standardized with

[0165] ascorbic acid minimum 6%

[0167] Bacillus coagulans from 1x10<9>CFU (Lyophilized culture up to 30 x10<9>CFU* of probiotics, 10 mg=1x10<9>CFU*)

[0168] *CFU - colony forming units

[0169] The vitamins and minerals are mixed with the following excipients per tablet: Xylitol from 100mg to 900mg Sodium carboxymethylcellulose from 1mg to 50mg Xanthan gum from 3mg to 150mg PVP from 1mg to 50mg Sucralose from 2mg to 50mg Acetosulfame K from 2mg to 30mg Steviol glycosides from 2mg to 30mg Flavoring powder from 10mg to 60mg Magnesium stearate from 2mg to 20mg Maltodextrin from 2mg to 30mg Beta-carotene 1% from 2mg to 30mg

[0171] Example 3

[0173] Pharmaceutical form: dispersible tablet

[0175] The composition of the active substances per tablet:

[0177] Vitamin C 500mg

[0178] as calcium ascorbate, 277mg

[0179] as sodium ascorbate, 281mg

[0180] Zinc 10mg

[0181] (as 48mg zinc picolinate)

[0182] Calcium threonate 10mg

[0184] Acerola Extract 10mg

[0185] (Malpighia glabra L.) standardized with

[0186] ascorbic acid minimum 17%

[0188] Rose extract 4mg

[0189] (Rosa canina L.) standardized with

[0190] ascorbic acid minimum 6%

[0192] Bacillus coagulans 1X10<9>CFU* (Lyophilized probiotic culture, 10 mg=1x10<9>CFU*)

[0193] *CFU - colony forming units

[0195] Vitamins and minerals are mixed with the following excipients per tablet: Xylitol 300mg

[0196] Sodium carboxymethylcellulose 6mg Xanthan gum 50mg Polyvinylpyrrolidone 33mg

[0197] Sucralose 35mg

[0198] Acetosulfame K 15mg

[0199] Steviol glycosides 12mg

[0200] Powdered perfume 10mg

[0201] Magnesium stearate 10mg

[0202] Maltodextrin 20mg

[0203] Beta-carotene 1% 15mg

[0205] Example 4

[0207] All ingredients were mixed in a Turbula free-fall mixer for 10 minutes, passed through a 0.8 mm mesh screen and compressed into tablets at 50 N to 90 N.

[0208] Tablet equipment: Rotary press

[0209] Tablet size/shape: 5mm-15mm/round

[0210] Tablet Evaluation

[0211] Total tablet weight 300mg -1500mg (1130mg)

[0212] Hardness 50N - 90N

[0213] Water activity * in tablet 0.09

[0214] Water content *8 in tablet 2.7%

[0215] *Nova Sina,

[0216] **Karl Fisher

[0218] The tablets have been studied for stability by storage for 18 months at conditions of higher (25%), medium (20%) and lower (10%) relative humidity and the viability of the microorganisms was monitored, with the following results (CFU/tablet):

[0219] Months 25% humidity 20% humidity 10% humidity

[0221] 0 1.8 * 10<9>1.6 * 10<9>1.9 * 10<9>

[0222] 6 1.6 * 10<6>1.4 * 10<8>1.7 * 10<9>

[0223] 9 1.4 * 10<5>1.1 * 10<8>1.5 * 10<9>

[0224] 12 1.2 * 10<4>1 * 10<6>1.4 * 10<9>

[0225] 18 <2 * 10<3>1.2 * 10<5>1.2 * 10<9>

[0227] Thus, it can be seen that the tablets of the invention provided excellent long-term stability.

[0229] Bibliography

[0231] 1. Prianka Chilukuri, Florence Odufalu, Christine Hachem, Dysphagia, Mo Med. 2018 May-Jun; 115(3): 206-210

[0232] 2. Vitamin C and contribution to the normal function of the immune system: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal 2015;13(11):4298

[0233] 3. Scientific Opinion on the substantiation of a health claim related to zinc and normal function of the immune system pursuant to Article 14 of Regulation (EC) No 1924/2006, EFSA Journal 2014;12(5):3653

[0234] 4. Jiang, Cao, et al (2020) Probiotic characteristics of Bacillus coagulans and associated implications for human health and diseases. Journal of Functional Foods, 64:103643. 5. Derse, P. H. and Elvehjem, C. A. Nutrient content of Acerola, a rich source of Vitamin C.

[0235] J. Am. Med. Assoc. 12-18-1954;156(16):1501

[0236] 6. Hanamura T, Mayama C, Aoki H, Hirayama Y, Shimizu M. Antihyperglycemic effect of polyphenols from Acerola (Malpighia emarginata DC.) fruit. Biosci Biotechnol Biochem 2006;70(8): 1813-20.

[0237] 7. Chrubasik, C., Duke, R. K., and Chrubasik, S. The evidence for clinical efficacy of Rose hip and seed: a systematic review. Phytother Res 2006;20(1):1-3

[0238] 8. Opinion on Calcium L-threonate for use as a source of calcium in food supplements, The EFSA Journal (2008) 866, 1-20

Claims (8)

1. Claims 1. The pharmaceutical composition of the orally dispersible tablets, which includes per tablet: spore-forming probiotic microorganisms Bacillus coagulans from 1x10<9>colony forming units (CFU) to 30x10<9>CFU, Vitamin C as sodium ascorbate and calcium ascorbate, from 80 mg to 1000 mg, zinc as zinc picolinate from 1 mg to 25 mg, calcium threonate from 5mg to 100 mg, Acerola extract from 1mg to 100mg and rose extract from 1mg to 100mg. 2. The pharmaceutical composition according to claim 1 which further comprises the following in the following amounts per tablet: Vitamin C from 80mg to 1000mg as calcium ascorbate, from 80 mg to 1000mg as sodium ascorbate, from 80 mg to 1000mg Zinc (as picolinate, gluconate, sulfate, etc.) from 1mg to 25mg Calcium threonate from 5mg to 100mg Acerola extract from 1mg to 100mg (Malpighia glabra L.) standardized with ascorbic acid minimum 17% Rose extract from 1mg to 100rng (Rosa canina L.) standardized with ascorbic acid minimum 6% Bacillus coagulans from 1X10<9>CFU to (Lyophilized culture 30 x 10<9>CFU of probiotics, 10 mg=1x10<9>CFU) Xylitol from 100mg to 900mg Sodium carboxymethylcellulose from 1mg to 50mg Xanthan gum from 3mg to 150mg PVP from 1mg to 50mg Sucralose from 2mg to 50mg Acetosulfame K from 2mg to 30mg Steviol glycosides from 2mg to 30mg Flavoring powder from 10mg to 60mg Magnesium stearate from 2mg to 20mg Maltodextrin from 2mg to 30mg Beta-carotene 1% from 2mg to 30mg 3. The pharmaceutical composition according to any one of claims 1 or 2 which further comprises the following amounts per tablet: Vitamin C 500mg as calcium ascorbate, 277mg as sodium ascorbate, 281mg Zinc 10mg (as 48mg zinc picolinate) Calcium threonate 10mg Acerola Extract 10mg (Malpighia glabra L.) standardized with ascorbic acid minimum 17% Rose Extract 4mg (Rosa canina L.) standardized with ascorbic acid minimum 6% Bacillus coagulans 1x10<9>CFU (Lyophilized culture probiotics, 10 mg=1x10<9>CFU) Xylitol 300mg Sodium carboxymethylcellulose 6mg Xanthan gum 50mg PVP 33mg Sucralose 35mg Acesulfame K 15mg Steviol glycosides 12mg Aromatic powder 10mg Magnesium stearate 10mg Maltodextrin 20mg Beta-carotene 1% 15mg The pharmaceutical composition of orodispersible tablets according to claim 3 with the water activity less than 0.2 and the water content of the tablet less than 4% by weight. 5. The Method of preparing orally dispersible tablets comprising zinc picolinate, calcium ascorbate, sodium ascorbate, Acerola extract, Rose extract, calcium threonate and Bacillus coagulans by following the steps: ● Mixing active ingredients zinc picolinate, calcium ascorbate, sodium ascorbate, acerola extract, rose extract, calcium threonate with sodium carboxymethylcellulose and xylitol in a free-fall blender for up to 10 minutes, passed through a sieve with a mesh size of 0.8 mm. ● Mixing lyophilized Bacillus coagulans powder with the previously prepared mixture in a free-fall blender, for 10 minutes. ● Mix PVP, sucralose, acesulfame K, steviol glycosides, beta-carotene and powdered flavor with the previously prepared mixture in a free-fall blender, for 10 minutes. ● Lubricate the mixture with magnesium stearate by mixing for 1 minute, passed through a sieve with a mesh size of 0.8 mm. ● Compress the bulk mixture into tablets at 50N to 90N. The composition according to any one of claims 1 to 3, the dispersion time in the mouth of the orally dispersible tablets is at least 2 minutes. 7. The pharmaceutical composition according to any one of claims 1 to 3 for use in a method of treating or ameliorating a disease associated with Vitamin C deficiency, zinc deficiency and general gastrointestinal and respiratory disorders, which comprises administering an effective amount of the composition to a subject suffering from or suspected of suffering from said disease. 8. The pharmaceutical composition according to any one of claims 1 to 3 for use in a method of treating or improving a condition or syndrome in a subject comprising administering to said subject an effective amount of the composition according to any one of claims 1 to 3, wherein said condition or syndrome is selected from the group consisting of diarrhea, antibiotic-associated diarrhea, bleeding gums, joint and muscle pain, more infections, feeling irritable, impotence, respiratory tract infections, eye problems, hair loss, nail changes, loss of appetite, weight loss, wounds that take a long time to heal, loss of taste and smell.