TR201615312A1 - Antiviral Pharmaceutical Compositions - Google Patents

Abstract

The present invention includes; Herpes zoster (shingles), epstein-Barr virus, genital herpes, genital herpes prophylaxis, herpes simplex virus type 1, herpes simplex virus type 2, postherpetic neuralgia, varicella-zoster virus prophylactic and / or symptomatic and / or suitable antiviral active ingredient and / or pharmaceutically acceptable derivatives thereof for use in therapeutic treatment, as monotherapy alone and / or in combination with other suitable active agents.

Description

DESCRIPTION ANTIVIRAL PHARMACEUTICAL COMPOSITIONS FIELD OF THE INVENTION The present invention; Herpes zoster (shingles), recurrent herpes in HIV-infected patients simplex, epstein-Barr virus, genital herpes, genital herpes prophylaxis, herpes simplex virus type 1, herpes siinplex virus type 2, postherpetic neuralgia, varicella-zoster be used in the prophylactic and/or symptomatic and/or therapeutic treatment of suitable active substance with antiviral properties and/or pharmaceutically acceptable derivatives are used alone as monotherapy and/or other with the appropriate active agent(s) and the pharmaceutical composition(s) for which it is used as a treatment to coinbine. The present invention; Famciclovir, 2- have acceptable derivatives, are used alone as monotherapy, and/or pharmaceuticals where this active ingredient is used as a combined treatment with other suitable agent/s relates to the composition/s.

Formula 1: In addition, the invention includes Famciclovir and/or its pharmaceutically acceptable derivativesiii It is used alone as monotherapy or when this active substance is combined with other suitable agent/s. for oral administration of pharmaceutical composition(s) used as combination therapy appropriate formulations and prophylactic and/or symptomatic and/or therapeutic includes their use. PRIOR ART (KNOWN STATE OF THE ART) Hepatitis B infection, on the other hand, is hepatitis, which is known as jaundice among the people. Hepatitis B virus, which belongs to the Hepadnaviridae family of viruses, causes (HBV) is a condition that occurs when it causes infection in the liver tissue.

Although HBV is a DNA Virus, it encodes the "reverse transcriptase" enzyme and this enzyme replicates via the RNA mediator (Summers and Mason. Cell 29: 403-415, 1982). It is found as a minichromosome in the eifected cell nucleus. covalently bound Intermediate molecule property called circular DNA during replication and transcription It has a complex replication strategy that consists of a DNA strand carrying has.

Chronic hepatitis B is an important health problem that concerns 400 million people in the world today. problem and one of the most common infectious diseases. According to the World Health Organization, One third of the world's population is infected with the hepatitis B virus and 5% of them are chronically ill.

About a quarter of these chronic patients have liver disease with fatal liver diseases. progresses to cirrhosis and liver cancer. Ultimately, 1 million people a year with hepatitis B dies from the virus. Severe symptoms and jaundice when the virus first enters the body It may not give any symptoms as well. Post-infection course full healing and life There may be long-lasting immunity, as well as chronicity and permanent liver disease and There may also be a transformation into liver cancer. chronic hepatitis B infection It significantly increases the risk of liver failure, cirrhosis and liver cancer. World Health Worldwide hepatocellular carcinoma of the hepatitis B virus (HBV) It is among the carcinogens that are responsible for 80% of the cases and affect humans. It has been reported to be in the second place after smoking (WHO/CDS/CSR/LYO/2002.2: Hepatitis It is among the serious liver diseases with morbidity and death rate worldwide. Pharmaceutical compounds used in the treatment of chronic hepatitis B virus infection; l. Immune modulators - Standard interferons and pegylated interferons 2. They are viral polymerase inhibitors.

I Nucleoside and nucleotide analogues Only about one-third of patients with long-term interferon alpha (IFN) virological response can be obtained and common side effects may prevent the use of this drug. strengthens it.

Examples of nucleoside and nucleotide analogues tested are penciclovir and its solid form. (FCV) [Vere Hodge, Antiviral Chem Chemother 4: 67-84, 1993; Boyd et al., Antiviral Chem Hepatitis 3: [Severini et al, Antimicrobial Agents can be given.

Shingles is an inflammation of the skin nerves with a painful rash. It is caused by the herpes zoster virus.

Herpes zoster Virus is transmitted in childhood and firstly it causes chickenpox, then it becomes nervous. years later, when the immune system weakens, it causes nerve inflammation.

The only natural source of the herpes simplex virus, which is widespread in the world, is human.

The disease is transmitted orally, mainly through infected tissue and secretions. maternally transmitted antibodies With its disappearance, primary infections begin in the first years of life. after recovery Despite the formation of antibodies, the virus does not separate from the organism and is a lifelong carrier. still emerges. If there is no primary infection in childhood, infection is not passed. On the other hand, 70-90% of adults have HSV-1 antibodies. ( Topçu AW, Söyletir G, Doganay M: Infection Diseases and Microbiology.

Herpes simplex virus (HSV) is one of the most common infectious viruses in the world.

There are two different types of HSV51s, type 1 (HSV-1) and type 2 (HSV-2). most common (0/o 857i of the society) HSV-1 infection in skin and mucous membranes outside the genital area causes illness. HSV-Z is a disease in the mucous and skin of the genital and anal region. doing. Herpes simplex virus (HSV), in immunocompromised patients, more frequently, more severely, and more frequently in direct proportion to the degree of immunodeficiency. chronic infections.

It makes it difficult for viruses to multiply in the cell and thus prevents viral diseases. Drugs that allow it to be overcome with milder symptoms are antiviral drugs.

Varicella-zoster virus (VZV) is an infectious agent that causes two different clinical pictures.

Varicella, or varicella, as it is commonly called; with diffuse exanthematous skin rashes Characterized as a result of exposure of people with a moderate course and not immune to the virus. is the primary disease. Primary infection in the organism if shingles or herpes zoster It is a recurrent infection of VZV, which remains latent after

Famciclovir is an orally administered antiviral agent. Precursor of penciclovir forensic antiviral agent it is medicine. Famciclovir is easily absorbed from the gastrointestinal tract and is higher in blood. levels remain. Because of this feature, like valaciclovir, longer interval daily It can be used in doses (Rudnick CM, Hoekzenia GS. Neonatal herpes simplex). Pharmaceutical compositions containing modified-release famciclovir are mentioned.

DESCRIPTION OF THE INVENTION The present invention; Herpes zoster (shingles), recurrent herpes in HIV-infected patients In the treatment of siinplexin, epstein-Barr virus, genital herpes, genital herpes prophylaxis, herpes simplex virus type 1, herpes simplex virus type 2, postherpetic neuralgia, varicella-zoster be used in the prophylactic and/or symptomatic and/or therapeutic treatment of suitable active substance with antiviral properties and/or pharmaceutically acceptable derivatives are used alone as monotherapy and/or other with pharmaceutical composition(s) used in combination therapy with appropriate active agent(s) Another aspect of the present invention is; suitable agent with antiviral properties for oral use substance and/or pharmaceutically acceptable derivatives alone as monotherapy used and/or combined treatment of this active substance with other suitable active agent/s It relates to the preparation of pharmaceutical composition(s) for which it is used.

The appropriate active substance with antiviral properties used in the invention is not limited to these. together; acyclovir, famciclovir, foscarnet, penciclovir, trifluridine, valaciclovir, idoxuridine and/or pharmaceutically acceptable derivatives, preferably famciclovir is selected as.

In the invention, the term "pharmaceutically acceptable derivatives" is defined as pharmaceutically acceptable. Suitable salts, esters, solvates, hydrates, complexes, polymorphs, enantiomers, prodrugs, acid addition salts, analogs, isomers, racemates, amides, enantiomer salts, basic salts, conjugates, tautomers, anhydrates, anhydrides, bases, one or more of acids, ethers, crystalline and amorphous forms or free forms is expressed.

The pharmaceutical composition prepared for oral administration may be in solid or liquid dosage forms.

These dosage forms are; tablet (uncoated, chewable, mouth soluble, dispersible, water dispersible, film coated, single layer, double layer, intestinal release coated, mini tablet, controlled release, sustained release, immediate release, extended release, delayed release release, modified release, buccal), capsule (hard, soft, enteric-coated, film-coated, controlled release, sustained release, immediate release, extended release, delayed release, modified release), powder, dry powder, granule, caplet, disc, mouth soluble film, bulk powder (multi-dose), pellet, sachet, water-dispersible powder, water-dispersible granule, effervescent tablet, effervescent granule, effervescent powder, microcapsule, dental tablets, pilula, syrup, solution, as a dosage form such as suspension, elixir, drops, position, emulsion, or spray. can be formulated.

The finished product is obtained by mixing the active substance and auxiliary substances in powder form. chassis can be formulated.

Some of the granules prepared for oral administration are swallowed, some are chewed, some are used by dissolving or dispersing in water or other suitable liquid.

Granules contain one or more active ingredients, excipients, color and fragrance if necessary. They also contain donor substances. They can also be prepared without any excipients. Granules single They can be packaged in dose or multidose form. Multi-dose preparations, at the desired dose They are packaged with a suitable scale so that they can be taken. Single dose granules bag, paper supplied in single-unit containers such as packs or vials. production, packaging, storage and their distribution should be carried out away from microbial contamination, Volatile or Granules containing substances to be protected should be stored in tightly closed containers.

Effervescent granules.' They are uncoated granules. Usually acid substances, carbonates or containing bicarbonates and reacting rapidly with water to release carbon dioxide are granules. It is dissolved or dispersed in water before application. As an active substance carrier they are used. It contains acidic substances such as citric acid, tartaric acid, fumaric acid in its formulations. they contain alkaline substances such as sodium carbonate, sodium bicarbonate and sodium biphosphate.

Coated granules.' They are mostly multi-dose preparations and various excipients. It consists of granules coated in one or more layers with their mixture. Coater Substances used as solvents are often in the form of solutions or suspensions and Applied in conditions where it is evaporated Proper release of active substance to coated granules A suitable dissolution test, for example, for solid dosage forms one of the tests described can be applied.

Modified release granules: The release rate, location or location of the active substance or substances. designed to modify the timing, containing special excipients, or They are coated or uncoated granules, individually or together, prepared by processes.

A suitable dissolution on these granules to show the mode of release of the active substance. test is applied.

Gastro-resistant granules: resistant to gastric fluid and Delayed, designed for the release of the active substance(s) in an intestinal fluid releasing granules. These properties are due to the fact that the granules are combined with a gastric fluid-resistant material. It is provided by coating (enteric coated granules) or by other suitable means. This an appropriate test on the granules to determine the appropriate release of the active substance. For example, one of the tests described for solid dosage forms can be applied.

Many techniques are used in the preparation of dosage forms. one of them granulation method. Granulation; as the growth of fine dust particles is defined. Granulation for pharmaceutical purposes; A preparation for tableting This is the stage of filling hard gelatin capsules or granules as a final product. It is also applied for the purpose of its use by being placed in a package.

The purpose of the granulation is to give the unit drug % of the particles of the powder substance participating in the mixture. is to create a unit of weight that will be equivalent to the quantities. Pharmaceutical powder mixes (active substance or auxiliary substances) in a unit by preventing their separation. It is necessary to ensure that they remain in a homogeneous form, this is achieved by granulation. possible.

The methods to be chosen in granulation can be classified in 3 main categories: wet granulation, dry granulation and other granulation methods.

Age Granulation; In the wet granulation method, high speed fluidized bed granulation, spray drying and extrusion pelletizing methods are used. Mourning In granulation, the active ingredient and the binder (solution) are mixed for a certain period of time. sieved and dried in a fluidized bed dryer. This dried mixture is the other filling. It is mixed with the ingredients until it reaches a certain homogeneity. My wife's last 3-5 slider is added in minutes. Samples are taken from the final mixture obtained and sent to the laboratory. sent. According to the results of the laboratory, for tablet compression or for the desired pharmaceutical form. stages can be passed.

Age granulation methods: 1. Age granulation method (Classical method) 2. Granulation by fluidized bed method 3. Granulation by Spray-Drying method 4. Microgranulation method . Extrusion-Spheronization method 6. Method of preparing granules with high-level mixers The wet granulation process is as follows: - Grinding the active ingredient (if necessary), - Mixing with powder substances, - Ensuring the aggregation of the particles of the powder mixture with the addition of binder, The process is called granulation.) - Screening of agglomerated particles as wet, - Drying of the sifted powder mixture is common in the drying process using bed dryers, - Homogenizing in double conical or V type mixers the mixture is called the final product) - It is the transition to tablet pressing or the stages for the desired pharmaceutical form.

Dry Granulation: In the dry granulation method, pre-compression and inter-roll compression methods are used. In dry granulation, it is usually 1/3 of the lubricant is mixed with other powder mixtures. This is because dust gets into the cylinders. prevents it from sticking. The remainder of the lubricant is added to the mix after dry granulation. and stirred for 3-5 minutes. Samples are taken from the final mixture formed after the mixture and It is sent to the laboratory for various tests. According to the laboratory results, tablet compression or Appropriate steps can be passed for the desired pharmaceutical form.

Tablet(s) prepared for oral use may contain one or more coatings.

coated tablets; The active ingredient is usually in the core, partially in the core and It is prepared in the form of formulas containing partially coating or only coating.

Coating materials must be physiologically harmless and incompatible with the active substance. should not be.

Coating types ; sugar coating, film coating and intestinal soluble (enteric) coating can be counted as

Sugar-coated tablets are compressed tablets having a coating consisting of sugar. are tablets. The coating may be colored and may have an offensive taste or coating of active substances with odor and sensitive to oxidation It is extremely useful in terms of protecting materials.

Film-coated tablets are a thin film applied using a water-soluble material. Compressed tablets coated with a layer or film. In line with this, the movie Maker A range of polymeric materials can be used with properties Film coatings, sugar Although it has the same general properties as the coatings, it is necessary for the coating process. It brings with it the important additional advantage of significantly reducing the time.

Purposes of Coating; - Masking off the offending odor and taste of the active ingredient - Correction of the aesthetic appearance of the tablet - Obtaining colored tablets with very little dyestuff - Increasing the easy swallowing of the tablet by the patient ° Increased mechanical strength during production, packaging and transportation - Protection of the active substance against digestive secretions ° Avoidance of side effects, eg stomach irritation - Facilitating the recognition of the drug, thus ensuring safety in drug use. increase - Increasing the stability of the active ingredient - It can be counted as being able to regulate the controlled release characteristics.

The pharmaceutical formulation(s) of the invention may contain one or more layers. Sufficient To ensure the therapeutic effect and to minimize the side effects, the release of the drug should be reduced. layer/s are changed, modified, controlled, extended, continuous, with one or more of the immediate or delayed release pharmaceutical dosage forms can be formulated.

Its pharmacokinetic properties are not in accordance with the user's expectations, for example half-life. short-lived, rapid/high peak with undesirable effects concentration, which is not well bioavailable for various reasons, etc. for drugs By changing the pharmaceutical forms, the release patterns in the gastrointestinal tract are aimed at the purpose. More optimized preparations are being developed. These have been changed many times, They are referred to as controlled, slowed and extended release formulations.

The compositions of modified release formulations are important for their function.

Modified-release drug formulations, although they may be more expensive, short half-life, peak, in which adherence to treatment is important for treatment success For drugs that reach concentration rapidly, with varying pharmacokinetics, They are useful and ultimately reduce the cost of treatment. Modified release systems They are classified as transdermal systems and oral systems. delayed release In systems, the release of the active substance from the system occurs in a certain region. Generally It is used for enteric coated tablets.

To increase the stability of the enteric coating formulation, to prevent acid-induced degradation. Expressed as substances or mixtures of substances used for these enteric coatings before it starts to decompose, it resists stomach acid and at the same time, it It provides a slow drug release in the upper part of the small intestine or in the upper part of the small intestine.

capsules; gelatin, cellulose esters, polyvinyl alcohol etc. for single dose medicine cone. They are containers made of one of the materials. Doses, solid and partial substances into capsules, Liquid drugs that do not dissolve the capsule can be placed. Capsules are generally divided into two; rigid/two-piece capsules and soft capsules.

Hard capsules consist of two parts: the container and the lid part. Bitter taste, swallowed capsules of difficult, air-perishable powders and drugs that are required to be rapidly absorbed. provided in. The main ingredient of hard gelatin capsules is a macromolecular It consists of high-value gelatin, which is a protein. Hard gelatin capsules gelatin, gum arabic, It is prepared from a mixture of paint and water with special techniques and special machines. hard capsules It is prepared by dipping method. The principle of this method is made of stainless steel on the surface of these rods by immersing them in the melted capsule wall solution. is the formation of the capsule wall film. Gelatin, dyes, preservatives and water, hard They are the substances that make up the gelatin capsule wall.

Hard capsules can be filled in powder, granule, pellet, tablet, liquid, and semi-solid forms.

There are two basic requirements for any formulation filled into capsules. The formulation must be filled in the correct dose and the active substance is released from the capsule for the treatment of the patient. should be released in sufficient quantity. For the preparation of hard gelatin capsule formulations active ingredient, fillers, flow improvers, glidaides, friction inhibitors, lubricants, dispersants, surfactants are used.

Soft capsules: single gelatin prepared with mixtures of glycerin, sorbitol, gum arabic and water. They are round, elliptical and tube-shaped capsules consisting of pieces. Required items After being placed, they are closed to not open. Soft capsules, gelatin of a liquid content It is prepared by enclosing it with the capsule wall. They are more flexible than hard capsules.

Soft capsules are round, oval, oblong (oblong stick) or tubular they may be. They consist of one piece. Soft gelatin capsules are usually included in solution or Liquid drug forms in suspension form are filled. However, semi-solids and powders are also can be filled. Production of soft capsules, insoluble substances, low-dose active substances, highly active compounds, oxygen sensitive substances, bad taste suitable for materials. In the production of soft gelatin capsules, the capsule wall a successive sequence of preparation, filling of the material and closure of the capsule. consists of the name.

Syrups are active in high skin solutions of sucrose or other sugars. liquid medicine formed by the dissolution of substances and auxiliary substances by various methods are shapes. Syrups prepared by dissolving only 64% sucrose in water It is called Simple Surup (Sirupus Simplex). The syrups contain 85% w/v sugar according to USP 24°.

In addition to sugar and other sweeteners, it is added to syrups to prevent crystallization, increase solubility. and adding sorbitol or glycerin to alter the taste and aromatic substances to impart flavor Preparation methods of syrups: - Prepared by simple thawing in hot or cold - Syrups prepared with extracts and tinctures - Prepared by maceration and digestion method - Syrups prepared with fruit juices - Prepared by percolation Resolution method can be listed as those prepared with.

The pharmaceutical formulation prepared for oral use in the present invention; pharmaceutically Acceptable suitable active ingredients as well as binder, dispersant, filler agent, buffering agent, surfactant, lubricant, glidant, diluent, preservative, flavoring agent, sweetening agent, viscosity increasing agent, antifoam agent, solubilizing agent, antistatic agent, wetting agent, pH adjusting agent, coloring agent, coating agent, solvent, softening agent, emulsifier, carrier, permeabilizing agent, antioxidant, chelating agent, alkalizing agent, photoprotective agent, thickening agent, isotonia adjusting agent, gelling agent, microbial preservative substance, curing agent, sivag, saline controlling agent, plasticizer, antiadherent, film Builder agent, opacifying agent, wetting agent, granulation solvent, suspension one or more excipients selected from the group including the agent and stabilizer Defines a composition that can contain

The term "binding agent" in the invention; keeping the ingredients together, tablets, pellets or ensuring that the granules are formulated with the required mechanical strength and low active dosage. expressed as substances or mixtures of substances used to give volume to units of is being done. As a binding agent; pregelatinized corn starch, pregelatinized starch, hydroxypropyl starch, gelatin, microcrystalline cellulose, cellulose, gums, polyvinyl pyrrolidone, polymethacrylates, sodium carboxymethyl cellulose, starch, paraffins, stearic acid, gums, methyl cellulose, ethyl cellulose, polyethyleneglycol, magnesium aluminum silicate, carboxy methylcellulose, hydroxy propylcellulose, hydroxy ethylcellulose, propylene glycol, polyoxyethylene- polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, polysaccharides, polaxamers, alginic acids, collagen, albumin, crospovidone, povidone, Copovidone, maltodextrin, hypromellose or mixtures of these can be used.

In the invention, the term "dispersant" means that the dosage form can be easily and quickly dissolved in water. It is expressed as substances that allow it to disperse. As a dispersant; agar agar, calcium carbonate, sodium carbonate, alginic acid, potato starch, corn starch, wheat Starches such as starch, pregelatinized starch, sodium starch glycolate, microcrystalline cellulose, cross-linked polyvinyl pyrrolidone, sodium alginate, hydroxypropyl cellulose, cross bound 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 their mixes can be used.

The term "filler" in the invention; practical, patient for the production of tablets or capsules as a substance or a mixture of substances used to be in a suitable size for its use is expressed. As a filler; talc, lactose, sucrose, dextrin, mannitol, lactilol, lactitol, xylitol, sorbitol, isomalt, microcrystalline cellulose, powdered cellulose, dextrose, dextrate, pregelatinized starch, modified starch, corn starch, lactose anhydrous, lactose monohydrate, dibasic calcium phosphate, silicic acid, kaolin, hydroxy propyl methylcellulose, tribasic calcium phosphate, polyhydric alcohols or cellulose ethers, calcium hydrogen phosphate dihydrate, calcium sulfate trihydrate, cellulose calcium sulfate, calcium sulfate dihydrate, maltodextrin, calcium carbonate, kaolin, sodium hydroxide or their mixtures can be used.

In the invention, the term "buffering agent" is used to regulate the acidity and basicity of the composition. referred to as items. As a buffering agent; citric acid anhydrous, sodium citrate dihydrate, sodium phosphate, sodium dihydrogei phosphate, potassium citrate, phosphoric acid, ammonium hydroxide, citric acid, diisopropanolamine, sodium carbonate, sodium silicate, disodium orthophosphate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium aluminate, diethanol amine, sodium alginate, ethylenediamine, meglumine, hydrochloric acid, lactic acid, sodium citrate, sodium hydroxide, triethanolamine, trolamine, sodium benzoate, sodium hydrogen carbonate or their mixtures can be used.

In the invention, the term "surfactant" is applied when dissolved in water or an aqueous solution. It refers to the chemical compound that affects the voltage. As a surfactant polysorbates, sodiumlauryl sulfate, sodium stearyl fumarate, non-ionic polyoxyethylene polyoxypropylene co-polymer, hexadecyl trimethyl ammonium bromide, alkyl polyethylene oxide, poloxainers, octyl glucoside, sugar esters and glycerides of fatty acids, dodecyl betaine, dodecyl diethylamine oxide, polyoxyl stearate, sodium stearate, polyethylene glycols, L-leucine, alkyl benzene sulfonate, fatty acids, quaternary ammonium compounds or mixtures thereof can be used.

"Lubricant" in the invention is the flow of a powder mixture that reduces or inhibits friction. It is expressed as agent or agent mixtures that improve its properties. lubricant aspect; 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, tripalmityl, 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 their mixtures can be used.

The term "glidant" in the invention; Tablet pressing immediately allows the flow of material into the matrix space. It is expressed as a substance with extra small particles and low density that facilitates it.

As a glidant; talc, magnesium stearate, hydrogenated vegetable oil, calcium stearate, stearic acid, colloidal silicon dioxide, sodium stearylfumate, polyoxyethyleneglycol, leucine, sodium benzoate, sodium chloride, sodium acetate, sodium fumarate, silica, colloidal anhydrous silica, polyethyleneglycol, cellulose derivatives, starch or their mixtures can be used.

The term "diluent" in the invention; practical, patient for the production of tablets or capsules as a substance or a mixture of substances used to be in a suitable size for its use is expressed. As a diluent; lactose, maltose, sucrose, dextrin, mannitol, lactylol, 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 their mixes can be used.

The term "preservative" in the invention; water and water-soluble, oil and fat-soluble substances It is expressed as substances that provide protection against microorganisms.

2-phenoxyethanol, sodium benzoate, benzoic acid, benzyl alcohol as preservatives, ethylenediaminetetraacetic acid, sodium methyl parahydroxy beiizoate, sodium propyl para hydroxy benzoate, sorbic acid, potassium sorbate, benzetonium chloride, chlorocresol, benzalkonium chloride, butyl paraben, methyl paraben, propyl paraben, ethyl paraben, butyl hydroxy aiiisol (BHA), butyl hydroxy tolueii (BHT), calcium acetate, citric acid, disodium edetate, glycerin, prOpil gallate, sodium bisulfite, sodium citrate, sodium metabisulfite, boric acid, sorbic acid, sodium propionate, propylene glycol or their mixtures can be used.

In the invention, the term "flavoring agent" is defined as substances used to add flavoring to the mixture. is being done. As a flavoring agent; natural essential oils (peppermint oil, wintergreen oil, parsley oil, orange oil, grape, citrus, grapefruit, lemon oil, etc.), orange flavor, banana flavor, peach flavor, grapefruit flavor, lemon flavor, apple flavor, strawberry flavor, vanilla flavor, mint flavor, tutti-furitti flavor, raspberry flavor, menthol, menthane, anethole, cinnamon, methyl salicylate, eucalyptal, sage, blackberry, citrus fruits or mixtures of these can be used.

As a "flavoring agent" in the invention; sodium saccharin, sucrose, D-glucose, galactose, xylose, maltose, maltodextrin, maltol, erythritol, lactitol, isomalt, isoinaltol, corn syrup, D- tryptophan, glycyrrhizic acid, monoammonium glycyrrhizinate, fructose, maltitol, dextrose, sucrose, xylitol, sorbitol, mannitol, lactose, aspartame, acesulfame potassium, neohesperidin dihydrochalcone, sucralose, sodium cyclamate or their mixtures can be used.

In the invention, the term “viscosity increasing agent” is used to increase the thickness of the liquid and to make it flow slowly. It is expressed as an agent or agent mixtures that provide Viscosity increasing agent aspect; xanthan gum, guar gum, acacia, povidone, alginic acid, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, cetyl alcohol, polyvinyl pyrrolidone, hydroxy propyl methyl cellulose, polydextrose, carrageenan, methyl cellulose, sucrose, sorbitol, xylitol, hydroxypropyl methylcellulose, polyvinyl alcohol, ketaryl alcohol, colloidal silicon dioxide or mixtures of these can be used.

In the invention, the term "antifoaming agent" refers to the initiation of the foaming reaction while the product is stored. as substances that stabilize the product against the water in the existing system by preventing is expressed. As antifoaming agent; sinethicone emulsion, dimethylsiloxane, silicone oil, monosodium carbonate, anhydrous trimagnesium dicitrate or mixtures thereof can be used. Antifoaming agent directly into effervescent granulated or external phase tablet It can be mixed with other excipients in powder form or made into both effervescent granules and tablets. It can be added to the excipient mixture by portioning.

As a solubilizing agent in the invention; sodium caseinate, polysorbate, methacrylic acid copolymer or mixtures thereof can be used.

The term "antistatic agent" in the invention; to reduce or eliminate static electricity in the content It is expressed as the substance or substance mixture used. The aforementioned antistatic as an agent; long chain aliphatic amines and amides, quaternary ammonium salts, phosphoric acid esters, polyethylene glycol esters, polyols, mono and diglyceride, fatty acid esters or mixtures of these can be used.

In the invention, the term "wetting agent" is readily available in the dispersion medium of hydrophobic drugs. It is expressed as substances used to help dispersal. slacker as substance; sodium lauryl sulfate, sodium docusate, polysorbates, sorbitan monolaurate, 0kt0xinol-9, nonoxynol-10, poloxamers, sodium carboxymethyl cellulose, bentonite, benzalkonium chloride, tetradecyltrimethyl ammonium bromide, cetylpyridineyuin chloride, glyceryl monostearate, macrogol cetostearyl ether, sorbitan tristearate, aluminiumi magnesium silicate or mixtures of these can be used.

In the invention, the term "pH adjusting agent" is used to regulate the acidity and basicity of the composition. referred to as items. As a pH adjusting agent; citric acid anhydrous, sodium citrate dihydrate, sodium phosphate, sodium dihydrogen phosphate, potassium citrate, phosphoric acid, ammonium hydroxide, citric acid, diisopropanolamine, sodium carbonate, sodium silicate, disodium orthophosphate, calcium carbonate, magnesium carbonate, magnesium hydroxide, magnesium aluminate, diethanol amine, sodium alginate, ethylenediamine, meglumine, hydrochloric acid, lactic acid, sodium citrate, sodium hydroxide, sodium chloride, triethanolamine, trolamine, sodium benzoate, sodium hydrogen carbonate or their mixtures can be used.

In the invention, the term "coloring agent" is a pleasant-looking and intermediate between the two formulations. They are expressed as substances that provide optical discrimination. Colorant as substances, but not limited to, yellow iron oxide, red iron oxide such as iron oxide pigments, ß-carotene, red beet powder, chlorophyll, tartrazine, yellow orange, quinoline yellow, erythrosine, titanium dioxide pigments, caramel, sunset yellow or mixtures of these can be used.

In the invention, the term "coating agent" describes the formulation content by moisture in the air. to protect against degradation and to facilitate swallowing unpleasant-tasting forms. It is expressed as the substance or substance mixture used. Coating agent aspect; methyl cellulose, hydroxyethylcellulose, hydroxybutylcellulose, hydroxypropylmethylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, carboxymethylethylcellulose, sodium carboxymethyl amylopectin, polyvinyl acetate phthalate, polyoxyethylene glycol, polyvinyl alcohol (opadry varieties), polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymer, methacrylic acid copolyiner, hydroxypropyl methyl cellulose acetate, dioxy methyl cellulose succinate, carboxy methyl ethyl cellulose, polyacrylic acids, methacrylic acid copolymers, methyl acrylate, ethylacrylate, methylmethacrylate, ethylmethacrylate, acrylic and methacrylic acid esters, hypromellose, hypromellose phthalate, hypromellose acetate succinate, hydroxymethyl cellulose succinate acetate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propyanate phthalate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate trimellitate, gelatin, celak, castor oil, chitosan, alginic acid, carrageenan, galactomanones, tragacanth, castor oil, gum arabic, guar gum, xanthan gum or their mixtures can be used. Such as purified water, ethyl alcohol, methyl alcohol, isopropyl alcohol, butyl alcohol as a solvent. alcohols, 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 inonoethyl ether, diethyl sulfoxide, diynethyl forrnamide, tetrahydroiran or mixtures thereof can be used, The term "softening agent" in the invention; water by forming a thin film on the skin It is expressed as substances that prevent it from flying. Vaseline as an emollient, solid petrolatum, liquid paraffin, sorbitol, glycerin, hydrocarbons, lanolin, waxes, fatty acids, cetyl alcohol, octyldodecanol, caprylic/capric triglyceride, cetyl stearyl alcohol, cocoa butter, diisopropyl adipate, glycerine, polyhydric alcohols and polyether derivatives, polyhydric alcohol esters, glyceryl monooleate, glyceryl stearate, linoleic acid, oleic acid, polypropylene glycol-1S stearyl ether (PPG-15 stearyl ether), polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene stearyl ether, propylene glycol stearate, stearic acid, stearyl alcohol, phospholipids, lecithin, steorols, cholesterol, cholesterol fatty acid esters and amides, urea, glyceryl monostearate, isopropyl myristate, isopropyl palmitate, ketostearyl alcohol, dimethicone, mineral oils, white solid paraffin, cetearyl alcohol or their mixtures can be used. Moreover herbal emollient such as castor oil, coconut oil, olive oil and vegetable waxes agents can also be used.

In the invention, the term "emulsifier" means homogeneous between two LV1 phases that do not mix with each other. are expressed as substances that provide dispersion. Polyethylene glycol as emulsifier stearate, polysorbate, polyglyceryl oleate, polyoxyethylene lauryl ether, ethoxylated lanolin, stearyl alcohol, cetostearyl alcohol, macrogol cetostearyl, glyceryl monostearate, cetyl alcohol, polyoxyethylene lauryl alcohol, polyoxy ethylene sorbitan monostearate, polyoxyethylene stearate, sorbitan inonostearate, propylene glycol stearate, aluminum starch octenylsuccinate, ammonia hydroxide, a white wax, a synthetic wax, carboiner, cetearyl alcohol, cyclomethicone, diglycerides, dimethicone, disodium monooleamido sulfosuccinate, pentaerythritol, glycerides, glyceryl monooleate, glyceryl stearate, lanolin, hydrogenated magnesium stearate, mineral oil, monoglycerides, polyethylene glycol, polyethylene glycol distearate, polyethylene glycol monocetyl ether, polyethylene glycol monostearate, polyoxyethylene glycol, polyoxyl cetostearyl ether, polyoxyl stearate, simethicone, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan palmitate, stearic acid, triethanolamine or sodium lauryl sulfates or their mixtures can be used.

Propylene glycol, purified water, castor oil, diisopropyl adipate, ethoxylated alcohol, fatty alcohol citrate, glycerine, hexylene glycol, isopropyl alcohol, isopropyl myristate, isopropyl palmitate, mineral oil, phosphoric acid, polyethylene terephthalate glycol, polyethylene glycol, polyethylene glycol inonostearate, polyoxyl ketostearyl ether, polyoxypropyleii stearyl ether, polysorbate, octyldodecanol, propylene carbonate, saturated fatty acid triglycerides, benzoic acid, ethanol or mixtures thereof may be used.

In the invention, the term "permeable material" refers to a substance that facilitates salivary penetration and thus creating a hydrophilic network that contributes to better dispersion of the tablet. referred to as items. Precipitated silicas as permeation agent, maltodextrins, ß-cyclodextrins or mixtures thereof may be used.

In the invention, the term “antioxidant” prevents oxidation caused by free radicals, are substances that have the ability to capture and stabilize free radicals. is being done. As an antioxidant; tocopherol (Vitamin E), ascorbic acid (Vitamin C), A Vitamins such as vitamin K, carotenoids, carotenes (eg (i-carotene, ß- carotene, lycopene, lutein, zeaxanthin), minerals (Se, Zn), butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT), ethylgalate, propylgalate, dodecylgalate, taurine, organosulfur compounds (allium, allyl sulfide, indoles), low molecular weight antioxidants (GSH-Px, uric acid) or mixtures of these can be used.

EDTA (ethylene diamine tetraacetic acid), disodium EDTA as chelating agent in the invention (disodium ethylene diamine tetraacetic acid) or calcium EDTA (calcium ethylene diamine) tetraacetic acid) or mixtures thereof can be used.

As an alkalizing agent in the invention; sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, primary amines, secondary amines, tertiary amines, cyclic amines, calcium glycerophosphate, calcium gluconate, calcium acetate, N,N, dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, disodium hydrogen orthophosphate, sodium aluminate, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium sulfate, monosodium glutamate, polakrillin sodium, sodium alginate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate, magnesium oxide or mixtures of these can be used.

As a photoprotective agent in the invention; iron oxide derivatives, metal oxides, titanium oxide or mixtures of these can be used.

In the invention, the term "thickening agent" refers to the resistance of formulations to various pressures and forces. are expressed as substances used for strengthening. thickening agent aspect; cetyl alcohol, aluminum stearate, dimethicone, cetearyl alcohol, stearyl alcohol, gum arabic, gum tragacanth, alginate, carrageenan, xanthan gum, guar gum, cetostearyl alcohol, cetyl esters wax, dextrin, glyceryl monostearate, hydroxypropyl cellulose, kaolin, polyethylene white petrolatum, propylene glycol stearate, starch, wax, white wax, bentonite, beeswax, white beeswax, synthetic wax, paraffin, white solid paraffin, white soft paraffin, solid Vaseline, pectin, carbomer, polyvinylpyrrolidone or their mixtures can be used.

In the invention, the term "isotonia adjusting agent" means the same osmotic pressure as the standard reference substance. referred to as substances. As the aforementioned isotonia adjusting agent; sodium chloride, mannitol, sorbitol, boric acid, potassium nitrate, glucose or their mixes can be used.

In the invention, carbopol, carbomer, hydroxy propylmethylcellulose, methylcellulose, sodium carboxymethylcellulose, polyacrylate polymers or their mixes can be used.

In the invention, the term "microbial preservative" protects against microbial activity. referred to as items. As the aforementioned microbial preservative; sodium benzoate, sodium methyl para hydroxybenzoate, sodium propyl para hydroxybenzoate, benzalkonium chloride, boric acid, sorbic acid, ethanol or their mixtures can be used.

In the invention, “hardening agent; The term means formulations against various pressures and forces. are expressed as substances used for strengthening. As a hardening agent; cetyl alcohol, aluminum stearate, dimethicone, cetearyl alcohol, stearyl alcohol, gum arabic, tragacanth gum, alginate, carrageenan, xanthan gum, guar gum, cetostearyl alcohol, cetyl esters wax, dextrin, glyceryl monostearate, hydroxypropyl cellulose, kaolin, polyethylene white petrolatum, propylene glycol stearate, starch, wax, white wax, bentonite, beeswax, white beeswax, synthetic wax, paraffin, white solid paraffin, solid petrolatum, pectin, carbomer, polyvinylpyrrolidone or mixtures thereof can be used.

As sivag in the invention; macrogol derivatives, petrolatum, wax modified vaseline, liquid petrolatum, white petrolatum, lanolin or lanolin derivatives, castor oil, coconut oil, olive oil, vegetable oils such as cottonseed oil, polyethylene glycol, paraffin, anhydrous, white soft paraffin or their mixtures can be used.

As "release controlling agent" in the invention; polyvinyl acetate phthalate, polyethylene glycol-polyvinyl alcohol copolyiner, polyacrylic acid derivatives, polysaccharide derivatives, methacrylate polymer, polymethacrylate, ethyl methacrylate copolymer, methacrylic acid-methylmethacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, polylactic acid, polylactic acid copolymer, polyvinylpyrrolidone, polyvinylalcohol, glyceride, polyethylene oxide, glyceryl behenate, methacrylic acid copolymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate, carboxy methyl ethyl cellulose, sodium carboxy methyl cellulose, ethyl cellulose, methyl acrylate, ethylacrylate, methylmethacrylate, ethylmethacrylate, acrylic and methacrylic acid esters, sodium alginate, hypromellose phthalate, hypromellose acetate succinate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propyanate phthalate, cellulose acetate phthalate, cellulose acetate Trimelitate, gelatin, celak, xanthan gum or their mixtures can be used.

In the invention, the term "plasticizer" is used to increase the flexibility of the coating, reduce the risk of film breakage. Expressed as substances used to reduce and increase the adhesion of the film to the core. They must be compatible with the polymer and not be volatile.

As a plasticizer; polyethylene glycols (Macrogol), glycerin, propylene glycol, acetyl citrate, aniyl oleate, myristyl acetate, butyl oleate, butyl stearate, triacetin, diethylphthalate, acetylated monoglycerides or mixtures thereof may be used.

In the invention, the term "antiadherent" refers to substances that prevent the formation of a rough tablet surface. is expressed. As an antiadherent; talc, colloidal silicon dioxide (Aerosil, Syloid, Cab-O-Sil), magnesium stearate, corn starch, magnesium trisilicate or their mixes can be used.

In the invention, the term "film-forming agent" refers to the use of a binder as a film, eg film or film. It is expressed as the necessary components to create it. As a film making agent; polyvinyl alcohol-partially hydrolyzed, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, Macrogol, gelatin or their mixtures can be used.

In the invention, the term "opacifying agent 7" refers to the additives added to make the desired system opaque. referred to as items. As an opacifying agent; titanium dioxide, calcium carbonate, zinc acetate, aluminum stearate, zinc stearate or mixtures thereof can be used.

The term "moisturizing agent" in the invention; the amount of moisture between the preparation and the air. are referred to as regulating and controlling substances. moisturizing agent aspect; glycerin, sorbitol, propylene glycol, urea, colloidal substances, liquid paraffin, petrolatum (petrolatum), liquid petrolatum, cellulose and cellulose-containing substances, gums (tragacanth), some electrolytes (Al salts, mercury salts borax) or their mixtures can be used.

In the invention, purified water, ethyl alcohol, methyl alcohol, isopropyl as granulation solvent Alcohols such as alcohol, butyl alcohol, methylene chloride or their mixtures can be used.

In the invention, the term "suspension agent" is used to increase viscosity and slow settling. used for the purpose. As a "suspension agent" in the invention, xanthan gum, guar gum, carrageenan, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), methyl cellulose or mixtures thereof can be used.

The term "stabilizer" in the invention; prevents crystallization or phase separation when added referred to as items. Benzoic acid, edetic acid, salicylic acid as stabilizer, sorbic acid, sodium dehydroacetate, tocopherol, butylated hydroxyanisole, butylated hydroxytoluene, propylgallate, castor oil, oleyl alcohol, poloxamer and poloxamines (polyoxyethylene and polyoxypropylene block copolymer), xanthan gum, sorbitan oil ethoxylated esters of acids, polysorbates such as polysorbate 80 or Tween 80, ethoxylated mono- and diglycerides, ethoxylated lipids, ethoxylated fatty alcohols or fatty acids, diacetyl phosphate, phosphatidyl glycerol, saturated or unsaturated fatty acids, sodium cholate, sodium glycolate, sodium taurocholate, paraoxybenzoic acid, tetraacetic acid of ethylene diaine acid (EDTA), diethylene triamine penta acetic acid or mixtures thereof can be used.

Appropriate active ingredient(s) and/or pharmaceutically acceptable in the present invention Famciclovir in pharmaceutical composition containing derivatives and/or pharmaceutically acceptable It is adjusted according to the individual needs of the patient and the assessment of the specialist.

The invention is mainly based on Famciclovir and/or antiviral drugs for oral use. where pharmaceutically acceptable derivatives are used alone as monotherapy and/or as a combined treatment of this active substance with other suitable active agent/s. relates to the preparation of the pharmaceutical composition(s) for which it is used. Your invention is prepared It is essential that pharmaceutical compositions are in tablet and/or capsule form. Like this, famciclovir and/or pharmaceutically acceptable derivatives of suitable pharmaceutical forms surprisingly very stable behavior in terms of physical and chemical stability has been observed.

Claims (1)

REQUESTS . Preparation of pharmaceutical compositions for oral use, in which the appropriate active substance with antiviral properties and/or its pharmaceutically acceptable derivatives are used alone as monotherapy and/or this active substance is used as a combined treatment with other suitable active agent/s. . It is a pharmaceutical composition/s as in claim 1 and its feature is; The antiviral active ingredient is selected among acyclovir, famciclovir, foscarnet, penciclovir, trifluridine, valaciclovir, idoxuridine and/or pharmaceutically acceptable derivatives. . It is a pharmaceutical composition/s as in claim 1 and its feature is; The antiviral agent inadden is preferably famciclovir. . It is a pharmaceutical composition/s as in claim 1 and its feature is; Tablet (uncoated, chewable, mouth-soluble, dispersible, water-dispersible, film-coated, monolayer, bilayer, intestinal release coated, mini tablet, controlled release, sustained release, immediate release, extended release, delayed-release, modified-release, buccal), capsule (hard, soft, enteric-coated, film-coated, controlled-release, sustained-release, immediate-release, extended-release, delayed-release, modified-release), powder, dry powder, granule, caplet, disc , mouth soluble film, bulk powder (multi-dose), pellet, sachet, water-dispersible powder, water-dispersible granule, effervescent tablet, effervescent granule, effervescent powder, microcapsule, dental tablets, pilula, syrup, solution, suspension, elixir, drops, It contains one or more pharmaceutical dosage forms selected from position, emulsion or spray. . It is a pharmaceutical composition/s as in claim 4 and its feature is; The pharmaceutical dosage form prepared for oral administration is preferably in the form of tablets and/or capsules. . It is a pharmaceutical composition/s according to any of the above claims and its feature is; The amount of Famciclovir and/or pharmaceutically acceptable derivatives in the pharmaceutical composition containing the appropriate active ingredient/s and/or its pharmaceutically acceptable derivatives is 10-100mg. . It is a pharmaceutical composition/s according to any of the above claims and its feature is; Herpes zoster (shingles), treatment of recurrent herpes simplex in HIV-infected patients, epstein-Barr virus, genital herpes, genital herpes prophylaxis, herpes simplex virus type 1, herpes simplex virus type 2, postherpetic neuralgia, prophylactic and/or symptomatic treatment of varicella-zoster virus and/or therapeutic treatment.