TR2022013352A2 - ORAL PHARMACEUTICAL FORMULATIONS - Google Patents

Abstract

The present invention; The appropriate active substance and/or pharmaceutically acceptable derivatives in the H1 receptor antagonist group and the appropriate active substance and/or pharmaceutically acceptable derivatives in the antihistamine group for use in symptomatic and/or prophylactic and/or therapeutic treatment to reduce the symptoms of dizziness and nausea related to vertigo disease. It relates to the pharmaceutical composition(s) comprising combination therapy with pharmaceutically acceptable derivatives thereof.

Description

DESCRIPTION ORAL PHARMACEUTICAL FORMULATIONS FIELD TO WHICH THE INVENTION CONCERNS The present invention; The appropriate active ingredient and/or pharmaceutically acceptable derivatives in the H1 receptor antagonist group and the appropriate active ingredient and/or antihistamine group to be used in symptomatic and/or prophylactic and/or therapeutic treatment to reduce the symptoms of dizziness and nausea related to vertigo disease. or pharmaceutically acceptable derivatives thereof. Present invention; The active substance in the group of Hi receptor antagonists, cinnariZin,1-benZhydryl-4-[(E)-3-phenylprop-2-enyl]piperaZin (Formula 1) and/or its pharmaceutically acceptable derivatives, the appropriate active substance in the group of antihistamines that the substance is dimenhydrinate, 2-benzhydryloxy-N,N-dimethylethanamine;8-chloro-1,3-dimethyl-7H-purine-2,6-dione (Formula 11) and/or its pharmaceutically acceptable derivatives. It relates to pharmaceutical composition/s in which the active ingredients are used in combination therapy with other suitable agent/s. Formula 1: Formula 11: H3EI3 H 0 Furthermore, the invention provides formulations of pharmaceutical compositions suitable for oral administration and prophylactic and/or symptomatic and It also includes/or therapeutic uses. PRIOR ART (STATE OF THE ART) Sinnarizin is an antihistamine drug used primarily to control vomiting due to motion sickness. Sinnarizin was first synthesized by Janssen Pharmaceutical in 1955. SinnariZin acts by blocking signal transmission between the vestibular apparatus of the inner ear and the vomiting center of the hypothalamus. The disparity in signal processing between inner ear motion receptors and the visual senses is eliminated, reducing confusion to the brain whether the individual is moving or standing. In motion sickness, vomiting is actually a physiological compensatory mechanism for the brain to adapt to the perception of signals to prevent the individual from moving. SinnariZin is an antihistamine and a calcium channel blocker. CinnariZin can also be viewed as a nootropic drug due to its vasorelaxing abilities occurring in the brain. Histamines mediate a number of activities, including contraction of the smooth muscle of the respiratory tract and the gastrointestinal tract, vasodilation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release, and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors can be divided into primary (sedating) and secondary (non-sedating) production substances. Some, such as CinnariZin, also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Thanks to its calcium channel blocking ability, SinnariZin also stimulates the vestibular system. SinnariZin inhibits the contraction of vascular smooth muscle cells by blocking L-type and T-type voltage-gated calcium channels. CinnariZin has also been associated with binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. Dimenhydrinate is a combination antiemetic drug containing diphenhydramine and theophylline. Dimenhydrinate directly blocks the stimulation of some nerves in the brain and inner ear to suppress nausea, vomiting and dizziness. Diphenhydramine and dimenhydrinate both reduce vestibular neuronal excitation due to angular and linear acceleration movements. The exact mechanism by which some antihistamines exert their antiemetic, antimotility sickness, and anti-vertigo effects is not known, but may be related to their central anticholinergic effects. They reduce vestibular stimulation and reduce the function of the labyrinth. An effect on the medullary chemoreceptive trigger zone may also be involved in the antiemetic effect. Dimenhydrinate is a competitive antagonist at the histamine H1 receptor, which is widely found in the human brain. It is thought that the antiemetic effect of dimenhydrinate is due to H1 antagonism in the vestibular system in the brain. DESCRIPTION OF THE INVENTION The present invention; The appropriate active ingredient and/or pharmaceutically acceptable derivatives in the H1 receptor antagonist group and the appropriate active ingredient and/or antihistamine group to be used in symptomatic and/or prophylactic and/or therapeutic treatment to reduce the symptoms of dizziness and nausea related to vertigo disease. or pharmaceutically acceptable derivatives thereof. In the invention, suitable active ingredient/s in the group of H1 receptor antagonists, including but not limited to the drugs used against dizziness, preferably cinnariZin and/or its pharmaceutically acceptable derivatives, among the drugs used against dizziness, betahistine, cinnarizin, Ilunarizin, acetilleucine and/or its pharmaceutically acceptable derivatives. is selected. In the invention, the active substance/s in the antihistamine group are toneZylamine, mepyramine, tenalidine, tripelenamine, chloropyramine, prometaZine, tolpropamine, dimetinden, clemastine, bamipine, isotypendil, diphenhydramine, dimenhydrinate, diphenhydramine methylbromide, chlorphenoxamine, bromaZine, diphenylpyraline, carbinoxamine, doxylamine, bromine. pheniramine, dexchlorpheniramine , chlorphenamine, pheniramine, dexbrompheniramine, talastin, histapyrodine, metapyrylene, alimemaZine, thiethylperazine, methydilaZine, hydroxyethylpromethazine, tiaZinam, mequitaZine, oxomemaZine, bukliZine, cycliZine, chlorcycline, meclozine, oxatomide, cetirizine, levosetiriZine, bamipin, cyproheptadine, fenindamine, antazoline, triprolidine , pyrrobutamine, azatadine, astemizole, terfenadine, loratadine, mebhydroline, deptropin, ketotifen, acrivastine, azelastine, tritoqualine, ebastine, pimethixene, epinastine, mizolastine, fexofenadine, desloratadine, rupatadine and/or pharmaceutically acceptable derivatives, preferably dimenhydrinate and/or Pharmaceutically acceptable derivatives are selected. In the invention, the term "pharmaceutically acceptable derivatives" means suitable pharmaceutically acceptable salts, esters, solvates, hydrates, complexes, polymorphs, enantiomers, prodrugs, acid addition salts, analogues, isomers, racemates, amides, enantiomer salts, basic salts, conjugates. , tautomers, anhydrates, anhydrides, bases, acids, ethers, crystalline and amorphous forms or one or more of their free forms are expressed. The pharmaceutical composition(s) prepared for oral administration may be in solid or liquid dosage forms. These dosage forms; tablet (chewable tablet, orally dispersible tablet, dispersible tablet, water-dispersible tablet, film-coated tablet, enteric tablet, mini-tablet, controlled-release tablet (sustained-release tablet, immediate-release tablet, extended-release tablet, delayed-release tablet) etc.), capsule (hard, soft, enteric-coated, film-coated), controlled-release capsule (sustained-release capsule, immediate-release capsule, extended-release capsule, delayed-release capsule), powder, granule, caplet, disc, orosoluble film, bulk powder (multi-dose), pellet, micropellet, sachet, water-dispersible powder, water-dispersible granule, effervescent tablet, effervescent granule, effervescent powder, gel, pill, syrup, solution, suspension, elixir, drop, position, emulsion or spray. The pharmaceutical formulation of the invention may comprise one or more layers of modified, controlled, extended, sustained, immediate or delayed release pharmaceutical dosage forms to provide control of the release of the drug to provide adequate therapeutic effect and minimize side effects. It can be formulated with or more. Coated tablets; It is generally prepared in the form of formulas containing the active ingredient in the core, partially in the core and partially in the coating, or only in the coating. Coating substances must be physiologically harmless and not incompatible with the active ingredient. Coating types; They can be listed as sugar coating, film coating and enteric coating. Sugar-coated tablets are compressed tablets that have a coating made of sugar. The coating in question may be colored and is extremely useful for covering active substances that have an offensive taste or odor and for protecting materials that are sensitive to oxidation. Enteric coatings are defined as substances or mixtures of substances used to increase the stability of the formulation and prevent acid-induced decomposition. These enteric coatings resist stomach acid before they begin to decompose and also provide a slow drug release in the lower part of the stomach or upper part of the small intestine. Film-coated tablets are compressed tablets coated with a thin layer or film applied using a water-soluble material. In this regard, a number of polymeric materials with film-forming properties can be used. Film coatings have the same general properties as sugar coatings, but bring with them the important additional advantage of significantly reducing the time required for the coating process. Purposes of Coating; ° Protection of the active ingredient against light, oxygen and moisture ° Masking of the undesirable odor and taste of the active ingredient ° Improving the aesthetic appearance of the tablet ° Obtaining colored tablets with very little dyestuff ° Increasing the easy swallowability of the tablet by the patient ° Increasing mechanical durability during production, packaging and transportation ° Protection of the active substance against digestive secretions ° Avoiding side effects, such as stomach irritation ° Facilitating the recognition of the drug, thus increasing the safety in drug use ° Increasing the stability of the active substance ° Regulating the controlled release characteristics. The pharmaceutical formulation(s) of the invention may contain one or more layers. The layer(s) may be formulated with one or more of a modified, modified, controlled, extended, sustained, immediate or delayed release pharmaceutical dosage forms to control the release of the drug to ensure adequate therapeutic effect and minimize side effects. Its pharmacokinetic properties do not comply with the usage expectations, for example, it has a short half-life, reaches a rapid/high peak concentration causing undesirable effects, does not have good bioavailability due to various reasons, etc. By changing the pharmaceutical forms of drugs, preparations are being developed whose release patterns in the gastrointestinal tract are made more suitable for the purpose. These are often referred to as modified, controlled, slowed and extended release formulations. The compositions of modified-release formulations are important for their functionality. Although modified-release drug formulations may be more expensive, they are more useful for drugs with short half-lives, rapid reaching peak concentrations, and variable pharmacokinetics, where patient compliance with treatment is important for the success of treatment, and in the final analysis, they reduce the cost of treatment. Modified release systems are classified as transdermal systems and oral systems. In delayed release systems, the release of the active substance from the system occurs in a certain region. It is generally used for enteric coated tablets. Enteric coatings are defined as substances or mixtures of substances used to increase the stability of the formulation and prevent acid-induced decomposition. These enteric coatings resist stomach acid before they begin to decompose and also provide a slow drug release in the lower part of the stomach or upper part of the small intestine. Direct compression consists of compressing the pulverized material without damaging the physical structure of the material. The excipient that has been widely studied as a direct compression medium is microcrystalline cellulose (Avicel, FMC). Many techniques are used in the preparation of dosage forms. One of these is the granulation method. Granulation; It is defined as the growth of fine powder particles. Granulation for pharmaceutical purposes; It is a preliminary preparation stage for tableting, it is also applied for the purpose of filling into hard gelatin capsules or placing the granule in a package as a final product. The purpose of granulation is to create a unit with a weight equivalent to the % amount of the unit drug of the particles of the powder material participating in the mixture. It is necessary to ensure that pharmaceutical powder mixtures (active ingredients or excipients) remain homogeneous within a unit by preventing them from separating, and this is possible with granulation. The methods to be chosen in granulation can be classified into 3 main categories: wet granulation, dry granulation and other granulation methods. Wet Granulation: In the wet granulation method, high-speed fluidized bed granulation, spray drying and extrusion pelletizing methods are used. In wet granulation, the active ingredient and binder (solution) are mixed for a certain period of time, sieved as wet and dried in a fluidized bed dryer. This dried mixture is mixed with other filling materials until a certain homogeneity is reached. Slider is added in the last 3-5 minutes of the mixture. Samples are taken from the final mixture and sent to the laboratory. Depending on the laboratory results, tablet printing or the desired pharmaceutical form steps can be taken. Wet granulation methods: 0 Wet granulation method (Classical method) 0 Granulation with fluidized bed method o Granulation with Spray-Drying method o Microgranulation method o Extrusion-Spheronization method 0 Granulation preparation method with high level mixers. The wet granulation process follows the following order: o Grinding the active ingredient (if deemed necessary), o Mixing with powder substances, o Ensuring the particles of the powder mixture clump together by adding binder, (This process is called granulation.) 0 Sieving the aggregated particles as wet, o Drying the sieved powder mixture. Using fluidized bed dryers widely in the drying process, C Dry grinding after the drying process, 0 Homogenizing in double cone or V type mixers o Adding lubricant to this mixture and mixing for another 5 minutes, (This mixture is called the final product.) 0 Tablet per press. or proceeding with the steps for the desired pharmaceutical form. Dry Granulation: In the dry granulation method, pre-compression and inter-cylinder compression methods are used. In dry granulation, generally 1/3 of the lubricant in the formula is mixed with other powder mixtures. This is because it prevents dust from sticking to the rollers. The rest of the lubricant is added to the mixture after dry granulation and mixed for 3-5 minutes. Samples are taken from the final mixture after mixing and sent to the laboratory for various tests. According to the laboratory results, the printing stages for the tablet or desired pharmaceutical form can be started. Capsules; gelatin, cellulose esters, polyvinyl alcohol, etc., for administering single doses of medication. They are containers made of one of the materials. Doses, solid and semi-prepared substances, and liquid drugs that do not dissolve the capsule can be placed in the capsules. Capsules are generally divided into two; hard/two-piece capsules and soft capsules. Hard capsules consist of two parts: the container and the lid. Powders that taste bitter, are difficult to swallow, and deteriorate quickly in the air, and drugs that require rapid absorption are intended to be given in capsules. The main ingredient of hard gelatin capsules consists of high-quality gelatin, which is a macromolecular protein. Hard gelatin capsules are prepared from a mixture of gelatin, gum Arabic, dye and water using special techniques and special machines. Hard capsules are prepared by the dipping method. The principle of this method is to dip rods made of stainless steel into the melted capsule wall solution and form a capsule wall film on the surface of these rods. Gelatin, dyes, preservatives and water are the substances that form the hard gelatin capsule wall. Hard capsules can be filled with powder, granules, pellets, tablets, liquids and semi-solid forms. There are two basic requirements for any formulation filled into capsules. The formulation must be filled into the capsule at the correct dose and the active substance must be released from the capsule in sufficient quantities to treat the patient. In order to prepare hard gelatin capsule formulations, active ingredients, fillers, substances that improve flow properties, glidants, antifrictions, lubricants, dispersants and surfactants are used. Soft capsules: They are single-piece round, ellipse and tube-shaped capsules prepared with a mixture of gelatin, glycerin, sorbitol, gum arabic and water. After the necessary items are placed, they are closed so that they cannot be opened. Soft capsules are prepared by surrounding a liquid content with a gelatin capsule wall. They are more flexible than hard capsules. Soft capsules can be round, oval, oblong (rectangular rod) or tube shaped. They consist of one piece. Soft gelatin capsules are generally filled with liquid drug forms in the form of solutions or suspensions. However, semi-solids and powders can also be filled. The manufacture of soft capsules is suitable for insoluble substances, low-dose active substances, compounds with high activity, oxygen-sensitive substances, and bad-tasting substances. In the production of soft gelatin capsules, preparation of the capsule wall, filling with material and closing the capsule consist of a series of sequential processes. In the present invention, pharmaceutical effervescent compositions for oral administration; Diluent/filler, binder, disintegrant, filler, effervescent couple, buffering agent, surfactant, lubricant, glidant, diluting agent, preservative, flavoring agent, sweetening agent, viscosity increasing agent, as well as suitable pharmaceutically acceptable active ingredients. , antifoam agent, solubility enhancing agent, antistatic agent, wetting agent, pH adjusting agent, coloring agent, carrier, coating agent, solvent, softening agent, emulsifier, carrier, permeating agent, antioxidant, chelating agent, alkalizing agent, photoprotective agent , one or more substances selected from the group including thickening agent, isotonia adjusting agent, gel-forming agent, microbial protective agent, thickening agent, sivag, release controlling agent, plasticizer, antiadherent, film-forming agent, opacifying agent, wetting agent and stabilizer. It defines a composition that may contain excess excipients. In the invention, the term "binding agent"; They are defined as substances or mixtures of substances used to hold the ingredients together, to ensure that tablets, pellets or granules are formulated with the required mechanical strength, and to give volume to low active dosage units. As a binding agent; pregelatinized corn starch, pregelatinized starch, hydroxy propyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxy methyl cellulose, starch, paraffins, stearic acid, gums, methyl cellulose, ethyl cellulose, polyethylene glycol, yum aluminum silicate , carboxy methylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, polyxamers, alginic acids, collagen, albumin, crospovidone, povidone, copovidone, maltodextrin , hypromellose or mixtures thereof may be used. Hydroxypropyl methyl cellulose is preferably used in the invention. The amount of binder used in the invention is 1-30% by weight. In the invention, the term "dispersing agent" is defined as substances that enable the dosage form to be dispersed easily and quickly in water. As a dispersant; starches such as agar agar, calcium carbonate, sodium carbonate, alginic acid, potato starch, corn starch, wheat starch, pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, cross-linked polyVinyl pyrrolidone, sodium alginate, hydroxypropyl cellulose, cross-linked hydroxypropyl cellulose, croscarmellose sodium, clay, ion exchange resin, crospovidone, xylitol, D-sorbitol, D-mannitol, lactose, sucrose, urea, high molecular weight polymers, povidone, alginic acid, xanthan gum, colloidal silicon dioxide or mixtures of these can be used. Corn starch and/or croscarmellose sodium is preferably used in the invention. The amount of dispersant used in the invention is 1-50% by weight. In the invention, "lubricants" are defined as agents or mixtures of agents that improve the flow properties of a powder mixture that reduces or prevents friction. As lubricant; talc, calcium stearate, magnesium stearate, aluminum stearate, polyethylene glycol, tristearin, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, polyoxyethylene glycol, oleic acid, tripalmythyl, potassium oleate, hydrogenated vegetable oils, leucine, alanine, glycine, caprylic acid, glyceryl behenate, glyceryl palmitostearate, sodium benzoate, sodium acetate, fumaric acid, zinc stearate, zinc oleate, zinc palmitate, paraffins, fatty alcohols or mixtures thereof can be used. Magnesium stearate is preferably used in the invention. The amount of lubricant used in the invention is 0.01-10% by weight. The term "glidant" in the invention; It is expressed as a low-density substance with extra small particles that facilitates the flow of the material into the matrix space during tablet pressing. As glidant; talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfurate, polyoxyethylene glycol, leucine, lethal, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, polyethylene glycol, cellulose derivatives , starch or mixtures thereof can be used. Preferably colloidal anhydrous silica and/or talc are used in the invention. The amount of glidant used in the invention is 0.01-10% by weight. The term "diluent" in the invention; It is expressed as substances or mixtures of substances used to make tablets or capsules practical for production and in a size suitable for patient use. As a diluent; lactose, maltose, sucrose, dextrin, mannitol, lactilol, xylitol, sorbitol, isomalt, microcrystalline cellulose, dextrose, dextrate, pregelatinized starch, modified starch, corn starch, lactose anhydrous, lactose monohydrate, dibasic calcium phosphate, hydroxy propyl methylcellulose, tribasic calcium phosphate, polyhydric alcohols or cellulose ethers, calcium hydrogen phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, maltodextrin, calcium carbonate, kaolin, sodium hydroxide or mixtures thereof may be used. Microcrystalline cellulose is preferably used in the invention. The amount of diluent used in the invention is 5-70% by weight. Purified water as solvent, alcohols such as ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol, acetone, diacetone, polyols, polyethers, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, or mixtures thereof may be used. The flow properties of powders, particle sizes, shapes and surface morphology are very important in the preformulation stage and can affect the content uniformity, homogeneity and dissolution rate of the formulation. Particle size and distribution can affect formulation characteristics, finished product specification and bioavailability of the product. For example, the sedimentation and flocculation rate of suspensions depends on the particle size. Additionally, in suspensions, crystal growth is more common in active substances with a wide particle size distribution range. Particle size and distribution are very important, especially in tablet and capsule technology. The particle size of active substances whose absorption is limited by the dissolution rate affects the absorption. As the particle size of powders changes, their specific surface areas also change. As a result, the dissolution rate of the drug in body fluids changes. The taste of the drug is also related to particle size. In preparing the solution formulation of a bitter-tasting drug for oral administration, it is not desirable to reduce the particle size too much. Because as the particles become smaller, the number of dissolved molecules increases. Determination of particle size and distribution is very important in the preformulation and formulation stages of a product. Particle size and distribution are determined by various methods. We can list the main methods as follows: a) Microscope method b) Sieve method c) Sedimentation method d) Coulter Counter and Hiac Royco method e) Laser diffraction method f) Light scattering method g) Gas permeability method h) BET adsorption method In particle size determination An appropriate method must be chosen. When determining the method, the amount of powder sample and the particle size range of the sample to be measured should be taken into account. Not every dust sample can be measured by every method. Additionally, there may be differences in the results depending on the shapes of the particles. As the particles move away from sphericity, different results are obtained. A large amount of powder sample is required for sieve analysis. Therefore it is not very convenient. Determination of very small particles is difficult. Although the microscope method is a suitable method for the analysis of small amounts of doses, particle counting under the microscope is tiring and there is a risk of error. The Coulter Counter device has a capillary flow cell. While the liquid containing the particles passes between two electrodes, the resistance of the liquid is continuously measured. Particle volume is measured depending on the change in electrical resistance. Recently, laser diffraction and light scattering methods, which are sensitive and can measure very small particles, have been used to determine particle size. Specific surface areas of particles are determined according to gas permeability and BET gas adsorption methods. Using both methods, when the particles are spherical, their diameters can also be found. The particle size for cinnarizine and/or its pharmaceutically acceptable derivatives used as the active ingredient in the prepared formulations of the invention is measured in the range of 10-100 µm for d(90), preferably 24 µm, more preferably 28 µm, and even more preferably 29 µm. 0 Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Dimenhydrinate. 0 Figure 2 shows an XRPD pattern of Cinnarizine. A representative X-ray powder diffraction (XRPD) pattern of cinnarizine is given in Figure 1. A representative X-ray powder diffraction (XRPD) pattern of dimenhydrinate is given in Figure 2. Thus, it has been surprisingly observed that the pharmaceutical composition of the invention with specific particle size distribution provides improvement in the characteristic properties of a formulation such as uniformity, solubility, formulation hardness, and has been found to have unexpectedly high physical and chemical stability and effectiveness. The tablet formulation for oral administration used in the invention; It describes a composition that may contain, in addition to suitable active ingredients, one or more pharmaceutically acceptable excipients selected from the group. It is essential that the pharmaceutical composition(s) of the invention prepared for oral administration be in tablet form. Thus, the pharmaceutical formulation/s obtained surprisingly exhibited a very stable behavior in terms of physical and chemical stability. They have also been observed to be surprisingly effective in providing sufficient therapeutic effect and minimizing side effects. The amount of cinnarizine and dimenhydrinate in pharmaceutical compositions containing the appropriate active ingredient of the present invention and/or its pharmaceutically acceptable derivatives; It ranges from 1 to 200 mg, preferably 20 mg for cinnarizine and 40 mg for dimenhydrinate, and is adjusted according to the individual needs of the patient and the evaluation of the specialist. Formulation examples for the pharmaceutical oral tablet composition comprising cinnarizine and dimenhydrinate and/or pharmaceutically acceptable derivatives thereof in the present invention illustrate, but do not limit, the invention. The tablet formulation for oral administration of pharmaceutical compositions using 20 mg Cinnarizine and 40 mg Dimenhydrate and their pharmaceutically acceptable derivatives for administration by oral tablet includes the following; - approximately 1-30% w/w Cinnarizine - approximately 1-50% w/w Dimenhydrate - approximately 5-70% w/w diluent - approximately 1-50% w/w disintegrant - approximately 1-30% binder at a w/w ratio - approximately 0.01-10% w/w glidant - approximately 0.01-10% w/w lubricant sufficient amount of solvent. The tablet formulation for oral administration of pharmaceutical compositions using 20 mg Cinnarizine and 40 mg Dimenhydrate and their pharmaceutically acceptable derivatives for administration by oral tablet includes the following; - approximately 1-30% w/w Cinnarizine - approximately 1-50% w/w Dimenhydrate - approximately 5-70% w/w Microcrystalline Cellulose - approximately 1-50% w/w corn starch and/or croscarmellose sodium - approximately 1-30% w/w hydroxypropyl methyl cellulose - approximately 0.01-10% w/w colloidal anhydrous silica and/or talc - approximately 0.01-10% w/w magnesium stearate - a sufficient amount of purified water. The tablet formulation for oral administration of pharmaceutical compositions for administration by oral tablet, using 20 mg Cinnarizine and 40 mg Dimenhydrate and pharmaceutically acceptable derivatives thereof, contains the following: (mg) - Cinnarizine in the amount of approximately 1 - 50 mg - Dimenhydrate in the amount of approximately 1 - 70 mg - approximately 5-120 mg Microcrystalline Cellulose - approximately 5-50 mg corn starch and/or croscarmellose sodium - approximately 1-50 mg hydroxypropyl methyl cellulose - approximately 0.01-10 mg colloidal anhydrous silica and/Or talc - approximately 0.01- 10 mg magnesium stearate - sufficient amount of pure water. Production process: Raw materials are weighed in accordance with the production formula. Sufficient amounts of Microcrystalline Cellulose and Cinnarizine are mixed (Mixing-l). Some of the remaining Microcrystalline Cellulose Corn Starch, Croscarmellose Sodium are mixed together (Mixing-2). The substances in Mixing-1 and Mixing-2 are sieved together and transferred to the granulator. The powder mixture is mixed. (Dry Mix I). A portion of hydroxypropyl methyl cellulose is mixed in pure water until it is completely dissolved. The wet granulation process is completed. The granules are dried in a fluidized bed dryer10. The dried granules are sieved (Dry Mix II). Dimenhydrinate, Microcrystalline Cellulose are mixed together (Dry mix III). One part of Hydroxypropyl methyl cellulose, one part of Croscarmellose Sodium, Colloidal Anhydrous Silica and Talc are mixed together. (Dry mix IV). Dry Mix III and Dry Mix IV are sieved together (Dry Mix V). Dry Mix II and Dry Mix V are mixed together to obtain the pre-lubricant mixture. Magnesium Stearate is sieved and added to the mixture before the slider and mixed. With the final mixture obtained, tablets are pressed using the appropriate Zimba.TR