CN116261457A - Film coated tablet for preventing and treating liver diseases - Google Patents

Film coated tablet for preventing and treating liver diseases Download PDF

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Publication number
CN116261457A
CN116261457A CN202180059270.8A CN202180059270A CN116261457A CN 116261457 A CN116261457 A CN 116261457A CN 202180059270 A CN202180059270 A CN 202180059270A CN 116261457 A CN116261457 A CN 116261457A
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China
Prior art keywords
coated tablet
coating agent
film
weight
polyvinyl alcohol
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CN202180059270.8A
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Inventor
韩恩志
李丙勋
韩成均
文炳官
赵佑炯
郑达沃
朴丹必
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Setron Pharmaceutical Co ltd
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Setron Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. fats
    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
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Abstract

The present invention relates to a film coated tablet for preventing and treating liver diseases, and more particularly, to a film coated tablet for securing stability and moisture-resistant effect of a composite active ingredient thereof. The film-coated tablet for preventing and treating liver diseases according to the present invention can ensure stability of the composite active ingredient and excellent moisture-resistant effect by coating the bare tablet containing the composite active ingredient with a film coating.

Description

Film coated tablet for preventing and treating liver diseases
Technical Field
The present invention relates to a film coated tablet for preventing and treating liver diseases, and more particularly, to a film coated tablet which ensures stability of composite active ingredients and has a moisture-resistant effect.
Background
The liver is the largest organ of the human body and has multiple functions. For example, the liver purifies blood, produces coagulation factors, stores and supplies the stored nutrients as necessary, and detoxifies or detoxifies drugs, foreign substances or poisons that enter the human body. In addition, the liver produces bile, which is a digestive enzyme. Therefore, when the liver is ill, digestion does not proceed well. The liver may be first attacked by alcohol or drugs, but it is difficult to detect such attacks early, as the signs of illness do not appear until the disease has progressed considerably. Only slight symptoms such as fatigue, dyspepsia, nausea, vomiting, anorexia, somnolence, boredom and the like appear, but jaundice appears when liver diseases progress for a little longer time.
Various drugs have been used for preventing and treating liver diseases. Examples of such drugs include: hepatocyte regeneration promoting agents and liver function supplements such as ursodeoxycholic acid, silymarin, glutathione, glycyrrhizin, liver extracts, multivitamins, etc.; antiviral drugs, such as Acyclovir (Acyclovir); immunosuppressants such as corticosteroids (corosoisoids), 6-mercaptopurine (6-Mercapto-prine, 6-MP), azathioprine, etc. (Azathioprine); fibrosis inhibitors such as D-penicillamine; direct hepatitis B and hepatitis C drugs, such as interferon, lamivudine, and adefovir.
Among the prior art related to prevention and treatment of liver diseases, korean patent application laid-open No. 10-2019-0046675 discloses a tablet comprising carnitine orotate, liver extract antitoxic component, xylylene dicarboxylate, adenine hydrochloride, pyridoxine hydrochloride, riboflavin, cyanocobalamin and excipients. However, when the tablet is prepared by the method described in the above patent document, since the tablet is not film-coated, the tablet is easily corroded by external moisture, and thus the stability of the preparation is remarkably lowered, and the stability of the active ingredient is also lowered.
Disclosure of Invention
Technical problem
It is therefore an object of the present disclosure to provide a film coated tablet having good stability of the composite active ingredient and good moisture resistance.
Technical proposal
1) There is provided a film coated tablet which is an uncoated tablet comprising a composite active ingredient comprising adenine or a salt thereof, an antitoxic component of liver extract, riboflavin, L-carnitine or a salt thereof, a cyanocobalamin-doubly powder, pyridoxine or a salt thereof, and a binaphthyl dicarboxylic acid ester and a pharmaceutically acceptable excipient. Alternatively, the film-coated tablet is a first coated tablet obtained by coating the outer surface of an uncoated tablet with a first coating agent comprising a polyvinyl alcohol-containing coating agent. Alternatively, the film-coated tablet is a second coated tablet obtained by coating the outer surface of the first coated tablet with a second coating agent comprising a polyvinyl alcohol-containing coating agent and a moisture barrier agent.
2) In one embodiment of the present invention, the excipient may include microcrystalline cellulose having a moisture content of 0.01 to 3% by weight.
3) In one embodiment of the present invention, the polyvinyl alcohol in the first coating agent may be 30 to 45% by weight or 33 to 40% by weight with respect to the total weight of the polyvinyl alcohol-containing coating agent.
4) In one embodiment of the present invention, the polyvinyl alcohol in the second coating agent may be 30 to 45% by weight or 33 to 40% by weight with respect to the total weight of the polyvinyl alcohol-containing coating agent.
5) In one embodiment of the present invention, the moisture barrier may be any one selected from mannitol, pregelatinized starch, erythritol, isomalt, xylitol, sorbitol, and maltitol.
6) In one embodiment of the present invention, the content of the first coating agent may be 1 to 10 parts by weight with respect to 100 parts by weight of the uncoated tablet.
7) In one embodiment of the present invention, the content of the second coating agent may be 1 to 10 parts by weight with respect to 100 parts by weight of the first coated tablet.
8) In one embodiment of the present invention, the moisture blocking agent may be contained in an amount of 5 to 50 parts by weight with respect to 100 parts by weight of the second coating agent.
9) In one embodiment of the present invention, the uncoated tablet may include: granules containing adenine or its salt, an antitoxic component of liver extract, riboflavin, and a pharmaceutically acceptable excipient; and a mixture comprising L-carnitine or a salt thereof, a cyanocobalamin-extender, pyridoxine or a salt thereof, a xylylene dicarboxylate, and a pharmaceutically acceptable excipient.
10 In one embodiment of the invention, the particles may be prepared by a dry granulation process.
In one embodiment of the invention, the invention may be a combination comprising any combination of element 1) and elements 2) to 10). For example, the present invention may be a coated tablet (1) comprising elements 1) and 2; a coated tablet (2) comprising elements 1), 2) and 3); coated tablet (3) comprising elements 1), 3) and 4); coated tablet (4) comprising elements 1), 3), 4) and 5); coated tablet (5) comprising elements 1), 2), 4) and 5); coated tablets (6) comprising elements 1), 6) and 7); coated tablets (7) comprising elements 1), 5) and 8); coated tablets (8) comprising elements 1), 9) and 10), and the like. However, the present invention is not limited thereto.
Advantageous effects
Film-coated tablets for preventing and treating liver diseases according to the present invention can be prepared by coating uncoated tablets containing a composite active ingredient with a film. Thus, the film-coated tablet is capable of stabilizing the composite active ingredient and has excellent moisture-resistant effect.
Detailed Description
The film-coated tablet according to an embodiment of the present invention is an uncoated tablet containing a composite active ingredient including adenine or a salt thereof, a liver extract antitoxic component, riboflavin, L-carnitine or a salt thereof, cyanocobalamin-doubler, pyridoxine or a salt thereof, and xylylene dicarboxylate, and a pharmaceutically acceptable excipient. The film-coated tablet is a first coated tablet obtained by coating the uncoated tablet with a first coating agent comprising a polyvinyl alcohol-containing coating agent. Further alternatively, the film-coated tablet is a secondary coated tablet obtained by coating the first coated tablet with a second coating agent comprising a polyvinyl alcohol-containing coating agent and a moisture barrier agent.
In the present invention, the uncoated tablet refers to a tablet that is compressed without coating.
In the present invention, the first coated tablet refers to a tablet obtained by first coating an uncoated tablet containing all active ingredients.
In the present invention, the secondary coated tablet refers to a tablet obtained by subjecting a first coated tablet to secondary coating.
In the present invention, the first coating agent means one or more components for the first coating, and the second coating agent means one or more components for the second coating.
[ Complex active ingredient ]
In one embodiment of the present invention, adenine or a salt thereof may be used as the complex active ingredient. Adenine (adenine) is a purine-based base that constitutes a coenzyme and a nucleic acid. Adenine is a precursor of coenzymes (NAD and FAD), which are components of the mitochondrial respiratory system and are also precursors of ATP as an energy source. Pharmaceutically acceptable salts of adenine include hydrochloride, sulfate, acetate, lactate, maleate, fumarate, succinate, tartrate, oxalate, citrate, benzenesulfonate, carbonate and borate. More specifically, the pharmaceutically acceptable salt may be, but is not limited to, hydrochloride or sulfate salts, and the like.
In one embodiment of the present invention, the complex active ingredient may use a liver extract antitoxic component (liver extract antitoxic fraction). The liver extract antitoxic component is an extract of amino acid aggregates obtained by hydrolyzing bovine liver. The anti-toxic component of liver extract provides essential amino acids required for liver cell proliferation, normalizes blood nitrogen balance, and has cholagogic effect.
In one embodiment of the present invention, riboflavin may be used as the composite active ingredient. Riboflavin (riboflavin) acts as vitamin B2, an important coenzyme (FAD) in the mitochondrial respiratory chain (mitochondria respiratory chain) and in fatty acid beta-oxidation.
In one embodiment of the present invention, the complex active ingredient may use L-carnitine (L-carnitine) or a salt thereof. L-carnitine or a salt thereof may exhibit excellent permeability to mitochondria of hepatocytes, prevent deterioration of damaged hepatocytes, and may be used to restore normal liver function. Examples of pharmaceutically acceptable salts of L-carnitine include L-carnitine orotate, L-carnitine naphthalene disulfonate, L-carnitine tartrate, L-carnitine fumarate, L-carnitine tartrate, L-carnitine succinate, L-carnitine hydrochloride, L-carnitine aspartate, L-carnitine citrate, L-carnitine phosphate, L-carnitine lactate, L-carnitine maleate, L-carnitine oxalate, L-carnitine dihydroxynaphthalene hydrochloride, L-carnitine sulfate, L-carnitine mucinate, L-carnitine 2-aminoethanesulfonate, L-carnitine methanesulfonate, L-carnitine trichloroacetate and L-carnitine trifluoroacetate. These substances may be used alone or in combination with other substances. However, the pharmaceutically acceptable salt of L-carnitine is not limited thereto.
In one embodiment of the present invention, L-carnitine or a salt thereof may include a solvate thereof, a crystalline form thereof, and the like.
In one embodiment of the present invention, cyanocobalamin (cyanocobalamin) doubler may be used as a composite active ingredient. The cyanocobalamin powder is prepared by grinding cyanocobalamin in proper excipient. More specifically, it means that a small amount of cyanocobalamin is ground by physical mixing or spray drying in one or more excipients selected from lactose, corn starch, mannitol, gelatin, maltodextrin, and the like. An example of a cyanocobalamin multiplier is a cyanocobalamin 100 multiplier, for a 100 wt% cyanocobalamin multiplier, the cyanocobalamin 100 multiplier contains 1 wt% cyanocobalamin and 99 wt% maltodextrin. In addition, the use of cyanocobalamin powder can help stabilize the composite active ingredient. In one embodiment of the present invention, pyridoxine (pyridoxine) or a salt thereof may be used as the complex active ingredient. Pyridoxine or its salts are vitamin B6, which can modulate the activity of transaminase (trans-aminase) which is a protein metabolism associated with hepatocytes, promoting the biosynthesis of carnitine. Examples of pharmaceutically acceptable salts of pyridoxine include hydrochloride, sulfate, acetate, lactate, maleate, fumarate, succinate, tartrate, oxalate, citrate, benzenesulfonate, carbonate or borate salts and the like. More specifically, the pharmaceutically acceptable salt may be, but is not limited to, a hydrochloride or sulfate salt.
In one embodiment of the present invention, the composite active ingredient may use a xylylene dicarboxylic acid ester (biphenyl dimethyl dicarboxylate, BDD). BDD is a fat-soluble component extracted from the seed interior of Schisandra chinensis (Schizandrae Fructus). BDD enhances cytochrome P450 activity of hepatocyte mitochondria, regulates immune response to prevent inflammatory necrosis of hepatocytes, and rapidly normalizes liver enzyme levels.
Excipient
In one embodiment of the invention, the excipient is a substance added to prepare a tablet having a regular form. The excipient may be used to ensure long-term storage stability, and the excipient may include one or more selected from maltodextrin, corn starch, microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, sodium starch glycolate, gelatin, hydroxypropyl cellulose, hypromellose, silicified microcrystalline cellulose, mannitol, and polyvinyl acetate. More specifically, the excipient may include microcrystalline cellulose having a low moisture content, wherein the moisture content is 0.01 to 3 wt% or 0.01 to 2 wt%, but is not limited thereto. In addition, the internal moisture content of the film-coated tablet is reduced to within the above moisture content range, contributing to the stability of the composite active ingredient.
In one embodiment of the present invention, the film coated tablet may further include pharmaceutically acceptable additives, and may include, but is not limited to, one or more selected from binders, disintegrants, lubricants, stabilizers, antioxidants, flavoring agents, gloss agents, colorants, pH adjusters, coating agents, sweeteners, adsorbents, solvents, masking agents, and surfactants.
[ coating agent ]
In one embodiment of the present invention, the film coated tablet comprises: a first coated tablet coated with a first coating agent comprising a polyvinyl alcohol coating agent; and a secondary coated tablet coated with a second coating agent comprising a polyvinyl alcohol coating agent and a moisture barrier agent.
In one embodiment of the present invention, the moisture barrier may include one or more selected from mannitol, pregelatinized starch, erythritol, isomalt, xylitol, sorbitol, and maltitol, and the secondary coated tablet contains the moisture barrier. Thus, the film-coated tablet has improved moisture resistance because the moisture barrier blocks moisture penetration from the outside. And the film-coated tablet has significantly improved formulation stability during long-term storage by ensuring stability of the composite active ingredient and preventing leakage of the composite active ingredient.
In one embodiment of the present invention, the polyvinyl alcohol in the first coating agent may be 30 to 45% by weight or 33 to 40% by weight with respect to the total weight of the polyvinyl alcohol-containing coating agent.
In one embodiment of the present invention, the polyvinyl alcohol in the second coating agent may be 30 to 45% by weight or 33 to 40% by weight with respect to the total weight of the polyvinyl alcohol-containing coating agent.
For example, opadry (Opadry), which is a coating agent containing polyvinyl alcohol, may contain 30 to 40 wt% polyvinyl alcohol.
In one embodiment of the present invention, the first coating agent is 1 to 10 parts by weight, 1 to 8 parts by weight, or 1 to 6 parts by weight with respect to 100 parts by weight of the uncoated tablet, but is not limited thereto.
In one embodiment of the present invention, the second coating agent is 1 to 10 parts by weight, 1 to 8 parts by weight, or 1 to 6 parts by weight with respect to 100 parts by weight of the first coated tablet, but is not limited thereto.
In one embodiment of the present invention, the moisture blocking agent may be contained in an amount of 5 to 50 parts by weight or 5 to 30 parts by weight with respect to 100 parts by weight of the second coating agent.
The content of the coating agent depends on the production efficiency. When the first coating agent and the second coating agent are used in large amounts, there is a problem in that the manufacturing time and cost increase and excessive increase in volume may cause a decrease in convenience in taking tablets. However, when the amounts of the polyvinyl alcohol and the moisture-blocking agent contained in the coating agent, the first coating agent and the second coating agent are within the above-described ranges, a film-coated tablet having little influence on dissolution rate, enhanced moisture resistance, improved stability of the composite active ingredient, and no leakage of the composite active ingredient can be obtained.
[ method for producing film-coated tablets ]
In one embodiment of the present invention, film coated tablets may be prepared by the following steps.
The preparation method comprises the following steps: a first step of preparing uncoated tablets containing adenine or a salt thereof, an antitoxic component of liver extract, riboflavin, L-carnitine or a salt thereof, cyanocobalamin-doubling agent, pyridoxine or a salt thereof, xylylene dicarboxylate and a pharmaceutically acceptable excipient; a second step of preparing a first coated tablet by coating the outer surface of the uncoated tablet with a first coating agent comprising a polyvinyl alcohol-containing coating agent; in a third step, a secondary coated tablet is prepared by coating the outer surface of the first coated tablet with a second coating agent comprising a polyvinyl alcohol coating agent and a moisture barrier agent.
In one embodiment of the invention, uncoated tablets may be prepared by mixing all of the following ingredients followed by tabletting: a granule comprising adenine or a salt thereof, an antitoxic component of liver extract, riboflavin, and a pharmaceutically acceptable excipient; and a mixture comprising L-carnitine or a salt thereof, a cyanocobalamin-extender, pyridoxine or a salt thereof, a xylylene dicarboxylate, and a pharmaceutically acceptable excipient. In the present invention, the uncoated tablet is prepared by a conventional uncoated tablet preparation method known to those skilled in the art, and the scope of the present invention is not limited by the uncoated tablet preparation method. The uncoated tablets mentioned in the present invention may be prepared, for example, according to the method described in korean patent No. 10-2193989. The granules may be prepared by dry granulation. Dry granulation includes a process of compressing a powdery component into a coherent compressed body (compact) having a large density, and a process of pulverizing the compressed body into fine particles of an appropriate size to obtain granules. Unlike wet granulation, since a liquid component such as a binder solution is not used, a drying process is not required. Therefore, the active ingredient is not exposed to moisture and heat, and thus the stability of the active ingredient is not deteriorated.
Examples
Embodiments will be described in more detail with reference to examples described below. However, these examples are provided for illustrative purposes only to aid in understanding the present invention, and the scope of the present invention is not limited by the following examples.
Film coated tablets were prepared with the ingredients and amounts listed in table 1 below.
EXAMPLE 1 preparation of double film coated tablets (1)
Preparation of uncoated tablets
The components listed in the following table 1 were mixed according to the method described in korean patent No. 10-2193989, and the mixture of components was tableted into uncoated tablets having a hardness of 10-20 kP using a tablet press (KT 10SS, manufactured by Keum Sung Machinery limited).
Preparation of film coated tablets
The uncoated tablets were loaded into a tablet coater (KC 50F, manufactured by Keum Sung Machinery limited) and first coated with a first coating agent obtained by dispersing opadry 200F280000 (trade name of Colorcon limited, containing 35% polyvinyl alcohol) in pure water. The first coating agent spraying conditions are as follows: the rotation speed of the fan is 18rpm, the pump speed is 3-5 rpm, the injection pressure is 3bar, the distance between the coating gun and the bottom surface of the tablet is 20cm, the air temperature is 60+/-5 ℃, and the product temperature is 40+/-2 ℃. After drying with the first coating agent, the first coated tablet was subjected to secondary coating with a second coating agent obtained by dispersing opadry 88a650041 (trade name of Colorcon, inc., 37% polyvinyl alcohol) and mannitol in pure water to produce a film-coated tablet. The spraying conditions of the second coating agent are as follows: the rotation speed of the fan is 18rpm, the pump speed is 3-5 rpm, the spraying pressure is 3bar, the distance between the coating gun and the bottom surface of the tablet is 20cm, the air temperature is 60+/-5 ℃, and the product temperature is 40+/-2 ℃.
TABLE 1
Content unit: mg of (mg)
Figure BDA0004113648960000081
EXAMPLE 2 preparation of double film coated tablets (2)
Film coated tablets were prepared in the same manner as in example 1 except that opadry 85F35210 (containing 40 wt% PVA) was used in place of opadry 88a650041 in the second coating agent.
Comparative example 1
Film coated tablets were prepared in the same manner as in example 2 except that only mannitol was excluded from the second coating agent.
Experimental example 1 evaluation of adenine hydrochloride content in film-coated tablet
[ adenine hydrochloride content measurement ]
The analysis method comprises the following steps: liquid chromatography
Column: inertsil ODS-3V 4.6x250mm,5 μm
A detector: absorbance detector (270 nm)
Mobile phase: acetonitrile in phosphate buffer = 80:20
Flow rate: 1.0mL/min
The film coated tablets of examples 1 and 2 and comparative example 1 were stored in PTP packages at 50±2 ℃ and 75±5% rh (severe test) for 4 weeks. Thereafter, the above stability test was performed to determine the adenine hydrochloride content. The results are shown in Table 2.
TABLE 2
Content unit: weight percent
Figure BDA0004113648960000091
As shown in table 2 above, examples 1 and 2 were found to exhibit excellent stability compared to comparative example 1.
Experimental example 2 evaluation of stability of film-coated tablets based on moisture content in excipient
Comparative example 2
Film-coated tablets were prepared in the same manner as in example 2 except that microcrystalline cellulose having a moisture content of 7% by weight was used instead of microcrystalline cellulose having a moisture content of 1.5% by weight.
Experimental example 2-1
The dry weight loss of the film-coated tablets of example 2 and comparative example 2 was measured using a halogen moisture analyzer "HB43-S" manufactured by Mettler Toledo. Drying was carried out at 105℃for 10 minutes. The results are shown in Table 3.
TABLE 3
Classification Example 2 Comparative example 2
Loss of dry weight (%) 1.55 3.34
Experimental example 2-2
After storage for 4 weeks under PTP packaging conditions, the film-coated tablets of example 2 and comparative example 2 were evaluated for adenine hydrochloride content in the same manner as in experimental example 1. The results are shown in Table 4.
TABLE 4
Content unit: weight percent
Figure BDA0004113648960000101
As shown in tables 3 and 4 above, microcrystalline cellulose having a moisture content of 1.5% by weight (example 2) reduced the internal moisture content of the film-coated tablets compared to microcrystalline cellulose having a moisture content of 7% by weight (comparative example 2). That is, it was confirmed that deterioration in stability of the complex active ingredient such as adenine hydrochloride was prevented.
Experimental example 3 evaluation of film-coated tablet stability according to the type of coating agent
Comparative example 3-1
Film coated tablets were prepared in the same manner as in example 2 except that opadry 03K19229 (containing 85% HPMC) was used instead of opadry 200F280000 (containing 35% PVC) in the first coating agent.
Comparative example 3-2
Film-coated tablets were prepared in the same manner as in comparative example 3-1 except that the first coating agent further contained the addition of 7 parts by weight of calcium silicate as a moisture absorbent per 100 parts by weight of the first coating agent.
Comparative examples 3 to 3
Film coated tablets were prepared in the same manner as in comparative example 3-1 except that opadry 03K19229 (containing 85% HPMC) was used instead of opadry 85F35210 (containing 40% PVA by weight) in the second coating agent.
Experimental example 3-1
After storage for 4 weeks under PTP packaging conditions, the film-coated tablets of examples 1 and 2 and comparative examples 3-1 to 3-3 were evaluated for adenine hydrochloride content in the same manner as in experimental example 1. The results are shown in Table 4.
TABLE 5
Figure BDA0004113648960000102
As shown in Table 5 above, examples 1 and 2 showed little change in adenine hydrochloride content as compared with comparative examples 3-1 to 3-3, indicating good formulation stability.

Claims (12)

1. A film coated tablet, characterized in that the film coated tablet is:
an uncoated tablet comprising a complex active ingredient and a pharmaceutically acceptable excipient, and the complex active ingredient comprises adenine or a salt thereof, an antitoxic component of liver extract, riboflavin, L-carnitine or a salt thereof, a cyanocobalamin-doubler, pyridoxine or a salt thereof, and a xylylene dicarboxylate;
a first coated tablet obtained by coating an outer surface of the uncoated tablet with a first coating agent comprising a polyvinyl alcohol-containing coating agent; and
a second coated tablet obtained by coating the outer surface of the coated tablet with a second coating agent comprising a polyvinyl alcohol-containing coating agent and a moisture barrier agent.
2. The film-coated tablet of claim 1, wherein the excipient comprises microcrystalline cellulose having a moisture content of 0.01 to 3% by weight.
3. The film-coated tablet of claim 1, wherein the polyvinyl alcohol in the first coating agent comprises 30 to 45% by weight relative to the total weight of the polyvinyl alcohol-containing coating agent.
4. The film-coated tablet of claim 3, wherein the polyvinyl alcohol in the first coating agent comprises 33 to 40% by weight relative to the total weight of the polyvinyl alcohol-containing coating agent.
5. The film-coated tablet of claim 1, wherein the polyvinyl alcohol in the second coating agent comprises 30 to 45% by weight relative to the total weight of the polyvinyl alcohol-containing coating agent.
6. The film-coated tablet of claim 5, wherein the polyvinyl alcohol in the second coating agent comprises 33 to 40% by weight relative to the total weight of the polyvinyl alcohol-containing coating agent.
7. The film-coated tablet of claim 1, wherein the moisture barrier comprises one or more selected from the group consisting of mannitol, pregelatinized starch, erythritol, isomalt, xylitol, sorbitol, and maltitol.
8. The film-coated tablet according to claim 1, wherein the content of the first coating agent is 1 to 10 parts by weight per 100 parts by weight of the uncoated tablet.
9. The film-coated tablet according to claim 1, wherein the content of the second coating agent is 1 to 10 parts by weight per 100 parts by weight of the first coated tablet.
10. The film-coated tablet according to claim 1, wherein the moisture-blocking agent is contained in an amount of 5 to 50 parts by weight per 100 parts by weight of the second coating agent.
11. The film-coated tablet of claim 1, wherein the uncoated tablet comprises:
granules containing adenine or its salt, an antitoxic component of liver extract, riboflavin, and a pharmaceutically acceptable excipient; and
comprises L-carnitine or a salt thereof, cyanocobalamin-type powder, pyridoxine or a salt thereof, a mixture of bi-xylylene dicarboxylic acid ester and a pharmaceutically acceptable excipient.
12. The film-coated tablet of claim 11, wherein the granules are granules prepared by a dry granulation process.
CN202180059270.8A 2020-07-22 2021-07-16 Film coated tablet for preventing and treating liver diseases Pending CN116261457A (en)

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