CN107970222B

CN107970222B - Oral compound preparation of metformin enteric-coated tablet coated with vitamin B layer and preparation method thereof

Info

Publication number: CN107970222B
Application number: CN201610922082.4A
Authority: CN
Inventors: 金拓; 冯佳; 吴飞
Original assignee: Beijing Xinde Runxing Technology Co ltd
Current assignee: Beijing Xinde Runxing Technology Co ltd
Priority date: 2016-10-21
Filing date: 2016-10-21
Publication date: 2021-01-08
Anticipated expiration: 2036-10-21
Also published as: CN107970222A

Abstract

The invention relates to a preparation method of an oral compound preparation which is released step by step at different digestive positions in a body, in particular to an oral compound preparation of metformin enteric-coated tablets coated by vitamin B layers and a preparation method thereof.

Description

Oral compound preparation of metformin enteric-coated tablet coated with vitamin B layer and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, relates to a preparation method of an oral compound preparation which is released step by step at different digestive positions in a body, and particularly relates to an oral compound preparation of metformin enteric-coated tablets coated with vitamin B layers and a preparation method thereof.

Background

Diabetes is a common disease that has been increasingly developed globally in recent years. Common agents for treating this disease include metformin (known primarily for its antihyperglycemic activity), and metformin hydrochloride (widely used in non-insulin dependent diabetes mellitus). Metformin hydrochloride is widely used in clinic, has low price, can be produced by a plurality of domestic medical units, has no patent right limitation, and is the hypoglycemic drug with the widest clinical application range at present.

Aplastic anemia is a disease with pancytopenia as the main clinical manifestation, and can occur in all age groups. In recent years, the number of patients with aplastic anemia in China has become younger and more year by year. In recent years, by using a gene expression database of aplastic anemia onset, a bioinformatics method and research results of pharmacogenomics, more than 3000 clinically common drug gene expression profile characteristics and gene expression profiles of aplastic onset are subjected to characteristic analysis, and metformin hydrochloride is found to have the effects of inhibiting the expression of aplastic onset related genes and promoting the expression of anti-aplastic related genes, which shows that: metformin hydrochloride may have an effect of treating aplastic anemia.

In the treatment of the above diseases, metformin hydrochloride is increasingly used clinically because the adverse reaction caused by the drug is mild. However, long-term use of the drug can cause adverse reactions, including increased blood cysteine concentrations. Because the increase of cysteine suggests that the incidence rate of cardiovascular and cerebrovascular diseases including coronary heart disease is increased, the long-term curative effect of patients is not ideal. Therefore, reducing the cysteine elevation caused by metformin hydrochloride will improve the curative effect of protecting cardiovascular function by reducing blood sugar. Vitamin B12 can reduce the side effect of metformin more remarkably, but diabetic patients are easy to get insufficient vitamin B12 from food due to the conventional dietary restriction.

Another adverse reaction of taking metformin hydrochloride for a long time is megaloblastic anemia, which is caused by the fact that metformin hydrochloride can inhibit the absorption of vitamin B12, and further causes megaloblastic anemia caused by the lack of hematopoietic raw materials, and peripheral neuropathy is caused. And the vitamin B12 can be used for treating the diseases, such as peripheral neuropathy, numbness of limbs, limb movement disorder, limited movement due to nerve function reduction, and incapability of self-care.

Therefore, in order to reduce the adverse reaction caused by the long-term application of the metformin hydrochloride, the metformin hydrochloride and the vitamin B12 are required to be prepared into a formula.

Currently, there are several regimens in which metformin and vitamin B12 are administered in combination: 1) mixing metformin hydrochloride and vitamin B12, adding corresponding adjuvants (such as starch, etc.), and making into tablet or capsule; 2) separately preparing metformin hydrochloride and vitamin B12 into separate preparations, and packaging in the same kit, wherein during use, patients can take the preparations sequentially, and 3) mixing the separated metformin hydrochloride and vitamin B12 preparations and then taking the preparations simultaneously.

According to the pharmacogenetic analysis, the vitamin B12 is mainly absorbed in the stomach, and the metformin hydrochloride is mainly absorbed in the small intestine with good effect. If the drug is taken according to the three schemes, the metformin hydrochloride is released in the upper digestive tract after oral administration, but can not be released in the positioning way of the small intestine, and can be subjected to enzymolysis in the stomach and can not avoid an enzyme barrier; in addition, the two active ingredients of vitamin B12 and metformin hydrochloride are absorbed simultaneously, metformin inhibits VB12 absorption, and new substances may be generated under the conditions of acidic pH and the presence of pepsin, which all result in the reduction of local drug concentration and bioavailability. At the same time, metformin hydrochloride also causes adverse irritation to the gastrointestinal tract. In order to ensure that the medicine taking is safer and more reliable and improve the local medicine concentration and bioavailability, the compound preparation which is designed according to the pH values and the protease properties of different digestive parts to release gradually at different digestive parts in vivo is required to be prepared.

Disclosure of Invention

Aiming at the technical problems, the invention designs according to the pH values and the protease properties of different digestion parts to prepare the compound preparation which is released step by step at different digestion parts in vivo.

Considering that vitamin B12 is mainly absorbed in stomach, metformin hydrochloride is mainly absorbed in small intestine, and the ratio of metformin to vitamin B in the drug formula is very different, if the metformin hydrochloride and the vitamin B are absorbed at the same time, the absorption of vitamin B12 is affected, so that the vitamin B is manufactured into a layer coated outside the metformin enteric coating layer, thereby achieving the purpose of the invention.

In order to ensure that the metformin hydrochloride tablet core in the compound preparation is stable and has high bioavailability, an enteric-coated tablet preparation mode is designed and adopted, the metformin hydrochloride tablet core is not released in the upper digestive tract but is released in the positioning way at the small intestine, and enzymolysis in the stomach is avoided, so that an enzyme barrier is avoided, the local drug concentration and bioavailability are improved, and meanwhile, adverse stimulation to the gastrointestinal tract is avoided. Furthermore, for the stability of the preparation, it is not the case that the enteric coating is directly coated outside the tablet core, but it is designed that an isolation coating layer is made between the tablet core and the enteric coating layer to obtain a stable compound preparation.

From the above, in the first aspect, the invention provides a method for preparing an oral compound preparation, wherein the preparation is gradually released at different digestion sites in vivo, and the method comprises the step of preparing the multi-layer components of the compound preparation according to the pH values and protease properties of the different digestion sites.

Specifically, the second technical scheme of the invention provides a preparation method of an oral compound preparation, wherein the oral compound preparation contains two or more than two effective components of medicines, and the mass ratio of any two effective components of the medicines is 1000: 1 or more.

Specifically, the third technical scheme of the present invention provides a method for preparing an oral compound preparation, wherein the oral compound preparation is a metformin enteric-coated tablet coated with a vitamin B layer, and the vitamin B and metformin are respectively released at different digestive positions step by step, and the preparation method comprises the following steps:

firstly, pressing a metformin tablet core, and then sequentially coating an isolation coating layer and an enteric coating layer outside the metformin tablet core to obtain a metformin enteric tablet; then, a vitamin B layer is coated outside the metformin enteric-coated tablet.

Specifically, the fourth technical scheme of the invention provides a preparation method of an oral compound preparation, wherein the oral compound preparation is a metformin enteric-coated tablet coated by a vitamin B layer, and the preparation method comprises the following steps:

1) the metformin tablet core is prepared from the following raw materials in the required weight per 1000 tablets:

mixing the components except the lubricant, adding water for granulation, wet granulation, drying, dry granulation, adding the lubricant for mixing, and tabletting to the hardness of more than 50kgf to obtain a metformin tablet core;

2) the isolating coating layer is prepared from the following raw materials in 1000 required weight:

dissolving the raw material compositions in a proper amount of water, and performing isolation coating on the metformin tablet core prepared in the step 1) to obtain an isolation coated tablet;

3) the enteric coating layer is prepared from the following raw materials in parts by weight per 1000 tablets:

dissolving the raw material compositions in a proper amount of water, and performing enteric coating on the isolated coated tablet prepared in the step 2) to obtain an enteric coated tablet;

4) the vitamin B layer is prepared from the following raw materials in 1000 tablets by weight:

dissolving the raw material compositions in a proper amount of water, and performing vitamin B layer coating on the enteric coating tablets prepared in the step 3) to obtain the metformin enteric coated tablets coated by the vitamin B layer.

Specifically, the fifth technical scheme of the invention provides a preparation method of an oral compound preparation, wherein the binder in the step 1) contains PVPK30 and HPMCK4M, the disintegrant is MCC101, the filler is pregelatinized starch, and the lubricant comprises magnesium stearate and aerosil;

the hydroxypropyl methylcellulose in the step 2-4) is Methocel E5 Premium, and the lubricant comprises PEG6000 and Talc; the diluent is TiO₂The methacrylic acid-ethyl acrylate copolymer is selected from opadry or ewing.

Talc refers to talcum powder.

The TiO is₂Namely titanium dioxide or titanium dioxide.

The vitamin B is selected from one or more of the group consisting of: vitamin B12, vitamin B1, vitamin B2, vitamin PP, vitamin B6, vitamin B5, vitamin B7, and vitamin B9.

Specifically, the sixth technical scheme of the invention provides a preparation method of the oral compound preparation, and the method further comprises the step of coating a light shading layer containing a light shading agent component outside the vitamin B layer.

In a second aspect, by the method of the first to the fifth aspects, a seventh aspect of the present invention provides a stable oral compound preparation of a metformin enteric coated tablet coated with a vitamin B layer, comprising a metformin tablet core, an isolation coating layer, an enteric coating layer and a vitamin B layer.

Specifically, the eighth technical scheme of the present invention provides an oral compound preparation, wherein the mass ratio of the metformin tablet core to the sum of the isolation coating layer, the enteric coating layer and the vitamin B layer is 100: 13-19; preferably, the mass ratio of the isolation coating layer to the enteric coating layer to the vitamin B layer is 1: 3-6: 0.5-2.

Specifically, the ninth technical scheme of the invention provides an oral compound preparation, wherein the metformin accounts for 60-85% of the whole oral compound preparation by mass; the mass ratio of the metformin to the vitamin B is 6000-40000: 1.

the inventors have specifically considered that the vitamin B group, especially VB12, is not photostable and is susceptible to degradation deactivation when applied as the outermost coating. Patients taking the compound preparation are all taking the medicine regularly, and the medicine is taken regularly by a common lightproof medicine box. Therefore, for the patient, for the purpose of prolonging the effectiveness of the medicament, a light-shielding layer is designed, in particular outside the vitamin B layer, which is made of an orally available pharmaceutical sunscreen material without toxic effects.

Specifically, the tenth technical scheme of the invention provides a preparation method of the oral compound preparation, which comprises a shading layer outside the vitamin B layer, wherein the shading layer comprises a chemical shading layer and/or a physical shading package; the light shading agent component of the chemical light shading layer is one or more than one of titanium dioxide, sunset yellow, carmine, indigo blue, iron oxide red and iron oxide yellow; the physical shading packaging product can be a PVC film, a PVC double-aluminum composite film or a PVC desiccant double-aluminum composite film.

Specifically, in the oral compound preparation, the tablet core consists of metformin hydrochloride, auxiliary materials such as a bonding agent, a disintegrating agent, a filling agent, a lubricating agent and a proper amount of water;

the isolation coating layer consists of hydroxypropyl methylcellulose, a lubricant and a proper amount of water;

the enteric coating layer consists of methacrylic acid-ethyl acrylate copolymer, a lubricant and a proper amount of water; and

the vitamin B layer consists of vitamin B, hydroxypropyl methylcellulose, a diluent, a lubricant and a proper amount of water.

When the vitamin B is preferably vitamin B12, the oral compound preparation obtained by the technical scheme can ensure that the vitamin B12 is mainly absorbed in the stomach and the metformin hydrochloride is mainly absorbed in the small intestine, so that the positive treatment effect of the metformin hydrochloride can be furthest exerted, including diabetes resistance and treatment of aplastic anemia, the symptoms related to adverse reactions are furthest reduced, the megaloblastic anemia caused by vitamin B12 malabsorption is prevented, diabetic peripheral neuropathy is prevented and treated, and the homocysteinemia caused by the increase of the concentration of cysteine in blood is effectively prevented.

The invention designs according to the pH value and the protease property of different digestive parts to prepare the compound preparation which is released step by step at different digestive parts in vivo, thereby combining a plurality of medicines with different functions or which are not suitable to be pressed in a tablet body into a whole, reducing the medicine quantity of patients to take, overcoming the problem that certain medicines can not be stored together during preparation, and increasing the stability of the compound preparation.

By arranging multiple layers of coatings with different functions, the compound preparation in the shape of a tablet is obtained, so that the compound preparation can be disintegrated, released and absorbed at different parts of the stomach and the intestine of a human body respectively, and the local drug concentration and the bioavailability are greatly improved. And the compound preparation has stable quality and can meet various requirements of clinical use.

Detailed Description

It is to be understood that the technical solutions described herein are for illustration purposes only and are not limiting, and that the specific scope of protection is subject to the claims.

Any numerical value recited herein includes from the lower limit value to the upper limit value. For example, if a concentration range is described as 0.01% to 50%, it is meant that values such as 0.2% to 40%, 10% to 30%, or 1% to 3% are expressly enumerated within this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between the lowest value and the highest value are to be considered to be expressly stated in this application.

Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. Now the definition is as follows:

definition of

The terms "vitamin B" and "VB" as used herein include, but are not limited to, vitamin B12 (including cobamamide, mecobalamin, cyanocobalamin, cobalamin), vitamin B1 (also known as thiamine, anti-beriberi vitamins), vitamin B2 (riboflavin), vitamin PP (also known as nicotinic acid or niacin, anti-pellagra vitamins), vitamin B6 (also known as pyridoxine, anti-dermatitis vitamins), vitamin B5 (pantothenic acid, also known as pantothenic acid), vitamin B7 (also known as vitamin H, biotin), vitamin B9 (also known as folic acid), and other members of the B vitamin family. Vitamin B7 indications: for dermatitis, eczema, atrophic glossitis, hyperesthesia, myalgia, lassitude, anorexia and mild anemia, alopecia), the effects include: help the normal synthesis and metabolism of fat, glycogen and amino acid in human body; promoting normal operation and growth of sweat gland, nervous tissue, bone marrow, male sexual gland, skin and hair, and relieving eczema and dermatitis; preventing canities and alopecia, and treating baldness; relieving muscle pain; promoting urea synthesis and excretion, purine synthesis and oleic acid biosynthesis; can be used for treating arteriosclerosis, apoplexy, lipid metabolism disorder, hypertension, coronary heart disease, and blood circulation disorder. The effects of vitamin B1 include: regulate sugar metabolism in vivo, and ensure that the staple food starch and sugar taken daily is converted into energy in human body for utilization. Optionally, vitamin complex, and indications including: peripheral neuritis, insomnia, restlessness; relieving nausea, emesis or vomiting of pregnancy caused by anticancer drugs and radiotherapy, and treating malnutrition, anorexia, tinea pedis, pellagra, and vitamin B deficiency.

The term "suitable amount" as used herein refers to a range that can be determined empirically by one skilled in the art, such as in a pharmaceutical pilot.

The term "excipient" as used herein includes agents for filling, binding, disintegrating and lubricating, and specifically includes the terms "filler", "binder", "disintegrant" and "lubricant" as used herein, and other excipients commonly used in the art.

The term "lubricant" as used herein is a broad concept in pharmacy and is a generic term for glidants, anti-adherents and (narrowly) lubricants, wherein: flow aids (Glidants) are substances that reduce the friction between particles and thereby improve the flowability of the powder; anti-sticking agent (anti) is substance to prevent the raw and auxiliary materials from sticking to the surface of the punch; ③ the lubricant is a substance which reduces the friction between the tablet and the wall of the hole of the die, which is a true lubricant. Thus, an ideal lubricant should combine the three aforementioned flow aiding, anti-stick and lubricating effects, but none of the currently available lubricants have such ideal lubricants that they tend to have better performance in one or both of these aspects, but relatively poor performance in the other. Adjuvants having any of the above-described effects are generally referred to collectively as lubricants according to customary classification methods. Examples of lubricants include: magnesium stearate; silica gel micropowder; talc powder; hydrogenated vegetable oil; polyethylene glycols and magnesium lauryl sulfate, and the like.

As used herein, the terms "opacifying layer", "opacifying layer" are used interchangeably and include chemical opacifying layers and/or physical opacifying packages available to those skilled in the art. The light shading agent component of the chemical light shading layer is one or more of titanium dioxide, sunset yellow, carmine, indigo blue, iron oxide red and iron oxide yellow. Titanium dioxide may be used as both an opacifier and a diluent. The physical sunscreen package can be selected from: the PVC film and the PVC double-aluminum composite film are packaged in the forms of PVC desiccant double-aluminum composite films and the like, and preferably, the PVC desiccant double-aluminum composite film is packaged.

As used herein, the terms "metformin hydrochloride" and "metformin" are used interchangeably.

The term "full test on quality standard" as used herein is performed with reference to national drug inspection standards.

The term "methacrylic acid-ethyl acrylate copolymer", as used herein, is a component of an enteric coating, which is used generically with the term "acrylic resin", and includes, without limitation, methacrylic acid and ethyl acrylate (1:1) copolymers, methacrylic resins, ethyl acrylate monomers, and the like. Can be used in the form of aqueous dispersion or as an alternative to coating solution of organic solution, etc. known to those skilled in the art.

For purposes of example, specific embodiments of the invention are described in detail below:

in a first aspect, the invention provides a method for preparing an oral compound preparation, wherein the preparation is released step by step at different digestion sites in a body, and the method comprises the step of preparing multi-layer components of the compound preparation according to the pH values and protease properties of the different digestion sites.

Specifically, the second technical scheme of the invention provides a preparation method of an oral compound preparation, wherein the oral compound preparation contains two or more than two effective components of medicines, and the mass ratio of any two effective components of the medicines is 1000: 1 or more, preferably 2000: 1 or more, more preferably 6000: 1 or more. The mass ratio of any two effective components of the medicine is preferably 1000-15000: 1; further preferably 2000 to 13000: 1; further preferably 5000 to 12000: 1; further 9000-11000: 1. the mass ratio of any two effective components of the medicine can be 1500: 1; 2000: 1; 2500: 1; 3000: 1; 3500: 1; 4000: 1; 4500: 1; 5000: 1; 5500: 1; 6000: 1; 6500: 1; 7000: 1; 8000: 1; 9000: 1; 11000: 1; 12000: 1; 13000: 1; 14000: 1; 15000: 1.

firstly, pressing a metformin tablet core, and then sequentially coating an isolation coating layer and an enteric coating layer outside the metformin tablet core to obtain a metformin enteric tablet; then coating a vitamin B layer outside the metformin enteric-coated tablet to obtain an oral compound preparation;

wherein the raw materials of the metformin tablet core comprise metformin, a bonding agent, a disintegrating agent, a filling agent and a lubricating agent; the raw materials of the isolation coating layer comprise hydroxypropyl methylcellulose and a lubricant; the raw materials of the enteric coating layer comprise methacrylic acid-ethyl acrylate copolymer and lubricant; the raw materials of the vitamin B layer comprise vitamin B, hydroxypropyl methylcellulose, a lubricant and a diluent.

the metformin is selected to be 250-305g in every 1000 tablets; the adhesive can be selected from 30-40 g; the disintegrating agent is 25-35 g; the filler is 15-25 g; the lubricant is selected from 1-3 g;

mixing the components except lubricant, granulating with water, wet granulating, drying, dry granulating, adding lubricant, mixing, and tabletting to hardness of 50kgf or more, such as 55kgf to obtain metformin tablet core;

in every 1000 tablets of medicine, the hydroxypropyl methylcellulose can be selected from 6-8 g; the lubricant is selected from 1.2-2 g;

dissolving the raw material compositions in a proper amount of water, and performing isolation coating on the metformin tablet core prepared in the step 1) to obtain an isolation coated tablet, wherein the mass of the isolation coated tablet is increased by 1.5-3.5%, preferably 2-3%, and preferably 2.5% relative to the mass of the metformin tablet core obtained in the step 1);

in every 1000 tablets of the medicine, 25-30g of methacrylic acid-ethyl acrylate copolymer can be selected; the lubricant is selected from 7-10 g;

dissolving the raw material compositions in a proper amount of water, and performing enteric coating on the isolated coated tablet prepared in the step 2) to obtain an enteric coated tablet, wherein the weight of the enteric coated tablet is increased by 8-12%, preferably 11% in terms of mass percentage relative to the mass of the metformin tablet core obtained in the step 1);

in every 1000 tablets of medicine, the hydroxypropyl methylcellulose can be selected from 6-8 g; the lubricant is selected from 1.2-2 g; vitamin B can be selected from 0.02-1g, preferably 0.02-0.1g, still preferably 0.02-0.05g, more preferably 0.02-0.04 g; the diluent can be selected from 0.5-3 g;

dissolving the raw material compositions in a proper amount of water, and coating the enteric-coated tablet prepared in the step 3) with a vitamin B layer to obtain the metformin enteric-coated tablet coated with the vitamin B layer, wherein the weight of the metformin enteric-coated tablet coated with the vitamin B layer is increased by 1-4%, preferably 2-3%, and preferably 2.5-2.9% in terms of mass percentage relative to the metformin tablet core obtained in the step 1).

the hydroxypropyl methylcellulose in the step 2-4) is Methocel E5 Premium, and the lubricant comprises PEG6000 and Talc; the diluent is TiO₂The methacrylic acid-ethyl acrylate copolymer is selected from opadry or ewing; the vitamin B is one or more selected from the group consisting of: vitamin B12, vitamin B1, vitamin B2, vitamin PP, vitamin B6, vitamin B5, vitamin B7, and vitamin B9.

Optionally, it is also provided in this embodiment that step 4 ') is followed by a further coating step 4'). The coating composition may be suitable for use with chemical or biological agents available according to the condition of the patient, including but not limited to prophylactic agents, therapeutic agents, nutritional agents, may be directed to a primary or concurrent disease of the patient, and in particular, may be other vitamins, and in particular other vitamin B. Can be used for adjuvant treatment of arteriosclerosis, apoplexy, lipid metabolism disorder, hypertension, coronary heart disease and blood circulation disorder, and has effects of relieving insomnia and restlessness, relieving nausea and emesis, and improving malnutrition and anorexia.

Alternatively, step 2 ') of making the release coating layer may be performed between step 4) and step 4').

Optionally, in the preparation method of the oral compound preparation provided by this technical solution, in step 1), the mass part ratio of the adhesive PVPK30 and the HPMCK4M is 1: 0.5-2, preferably 8: 5; the methacrylic acid-ethyl acrylate copolymer in the step 3) is EUDRAGITL 30D-55.

The PVPK30, HPMCK4M, MCC101, Methocel E5 Premium, PEG6000, Opadry or Eudragit (EUDRAGITL) (such as EUDRAGITL30D-55) are all commercial pharmaceutical excipients.

Optionally, the technical scheme also provides that a coating layer is coated outside the vitamin B layer. The coating composition may be suitable for use with chemical or biological agents available for use in accordance with a patient's condition, including but not limited to prophylactic agents, therapeutic agents, nutritional agents, may be directed to a primary or concurrent disease of a patient, and in particular, may be other vitamins, and in particular other vitamin bs. Can be used for adjuvant treatment of arteriosclerosis, apoplexy, lipid metabolism disorder, hypertension, coronary heart disease and blood circulation disorder, and has effects of relieving insomnia and restlessness, relieving nausea and emesis, and improving malnutrition and anorexia.

Optionally, a barrier coating layer is present between the vitamin B layer and the coating layer outside it.

Specifically, the eighth technical scheme of the present invention provides an oral compound preparation, wherein the mass ratio of the metformin tablet core to the sum of the isolation coating layer, the enteric coating layer and the vitamin B layer is 100: 13-19, more preferably 100: 15-17, even more preferably 100: 16; preferably, the mass ratio of the isolation coating layer to the enteric coating layer to the vitamin B layer is 1: 3-6: 0.5 to 2, and more preferably 1: 4-5: 0.8 to 1.5, more preferably 1.2: 5.5: 1.4.

specifically, the ninth technical scheme of the invention provides an oral compound preparation, wherein the metformin accounts for 60-85% of the total oral compound preparation by mass, can be selected from 60-65%, and further preferably from 61-63%; the mass ratio of the metformin to the vitamin B is 6000-40000: 1, preferably 7000 to 20000: 1, more preferably 8000 to 15000: 1, more preferably 9000-12000: 1.

the inventors have specifically considered that the vitamin B group, especially VB12, is not photostable and is susceptible to degradation deactivation when applied as the outermost coating. Patients taking the compound preparation are all taking the medicine regularly, and the medicine is taken regularly by a common lightproof medicine box. For the patient, therefore, for the purpose of prolonging the effectiveness of the medicament, a light-shielding layer is provided, in particular outside the vitamin B layer, which is made of an orally available, non-toxic sunscreen.

Examples

The present invention will be described more specifically below by way of examples. While the following examples provide further detailed descriptions of some of the embodiments of the present invention, they are to be considered as merely illustrative and not limiting in any way the invention as defined by the appended claims. Those skilled in the art can make various modifications and improvements within the technical concept of the present invention.

Preparation example 1

1. Compound medicament general formula

2. Process flow

Firstly, pressing a metformin tablet core, and then sequentially coating an isolation coating layer and an enteric coating layer outside the metformin tablet core to obtain a metformin enteric tablet; and then coating a vitamin B layer outside the metformin enteric-coated tablets to obtain the oral compound preparation.

2.1 preparation of metformin Tab cores

1) Metformin tablet core formula

The tablet weight is 350mg, and each tablet contains 250mg of metformin. The experimental batch was 20 ten thousand pieces (i.e., 70 kg).

2) Tabletting process and operation

Weighing: weighing the materials (except magnesium stearate and silica gel micropowder) according to the proportion, and sieving with a 60-mesh sieve if the materials are agglomerated;

mixing: mixing the materials in the first step in a high-speed stirring granulator for 5-10 minutes;

③ granulating: uniformly mixing the materials, adding a proper amount of water, stirring and granulating, and pressing the mixture into particles which are crushed when the materials are tightly held into a cluster;

wet granulation: carrying out 16-mesh sieve granulation on the wet granules in the third step by using a swinging granulator;

drying: drying the finished wet particles in an oven until the LOD is less than 2%;

sixthly, dry granulation: using a swing type granulator to perform 20-mesh sieve granulation on the dried granules;

and (c) mixing: adding magnesium stearate and superfine silica gel powder into the dried granules according to the proportion, and mixing for 1-3min in a mixer.

Eighthly, tabletting: and c, punching the mixed particles into round pieces with the weight of 350mg (+ -5%) and the hardness of over 50kgf in a shallow arc of 10 mm.

2.2 coating of an isolation coating

1) Formula of isolating coat coating liquid

2) Preparing isolation clothes liquid

Dissolving Methocel E5 Premium and PEG6000 in water 7-12 times (preferably 9 times) respectively, and mixing uniformly.

② Talc to add 3-5 times (preferably 4 times) of water to carry out homogenization and dispersion for 10 minutes.

And thirdly, merging the second step into the first step, merging the rest water washing containers, and stirring uniformly to obtain the isolation clothes liquid.

3) Isolating coating layer

The metformin tablet core, referred to above, was placed in an O' HaraLabcoatI high performance coating pan and an isolation coating layer was applied using an infusion pump, Watson 505U. The temperature of the inlet air is controlled to be 58-60 ℃, and the air quantity is controlled to be 110m³The pot rotating speed is 3-7rpm, the pump rotating speed is 5-9rpm, the average liquid spraying speed is 8.4g/min, the material temperature is 31-35 ℃, the atomizing pressure is 0.2MPa, the fan surface pressure is 0.2MPa, the air outlet temperature is 36-39 ℃, and the negative pressure is-0.2 cmH₂And O. After the barrier coating is completed, the tablet cores are dried in a coating pan at low pan speed for 8-15 minutes.

2.3 enteric coating

1) Enteric coating liquid formula

The tablet core coated with the isolation coating is continuously coated with enteric coating according to the following formula.

2) Preparing enteric coating liquid

PEG6000 is dissolved in 3-5 times (preferably 4 times) of water and then homogenized for 10 minutes together with Talc Talc suspension prepared by adding 3-5 times (preferably 4 times) of water.

Secondly, slowly pouring the suspension liquid I into the stirred and diluted EUDRAGITL30D-55, and uniformly stirring to obtain the enteric coating liquid.

3) Enteric coating layer

The barrier coated tablets were placed in the coating pan as described above and enteric-coated using the infusion pump as described above. The inner diameter of the silica gel infusion tube is 3.1mm, the air inlet temperature is controlled to be 58-60 ℃, and the air volume is 110m³The pot rotating speed is 4-7rpm, the pump rotating speed is 6-10rpm, the average liquid spraying speed is 7.7g/min, the material temperature is 27-30 ℃, the atomizing pressure is 0.18MPa, the sector pressure is 0.18MPa, the air outlet temperature is 34-37 ℃, and the negative pressure is-0.2 cmH₂O。

After the enteric coating is completed, the tablet cores are dried in a coating pan for 8-15 minutes at low pan speed.

2.4 layer VB12 bag

1) VB12 layer coating liquid formula

Each metformin tablet should contain 26.5 μ g (+ -5%) of VB12, and due to the loss of the medicine, the VB12 layer is coated in an amount which is 1.1 times of the amount of the formula, and the VB12 raw material needs to be operated and stored in a dark place.

2) Preparing VB12 layer liquid

Dissolving Methocel E5 Premium and PEG6000 in 5-20 times of water respectively, and then mixing uniformly.

②Talc、TiO₂And VB12 were added to 3 to 5 times (preferably 4 times) of water to conduct the homogenization and dispersion for 10 minutes.

And thirdly, merging the second step into the first step, merging the rest water washing containers, and stirring uniformly to obtain VB12 layer liquid.

3) Layer VB12 package

The metformin enteric-coated tablets were put into the coating pan as described above, and VB12 layers were further coated using the infusion pump as described above. The inner diameter of the silica gel infusion tube is 3.1mm, the air inlet temperature is controlled to be 58-60 ℃, and the air volume is 100m³The pot rotating speed is 4-7rpm, the pump rotating speed is 7rpm, the average liquid spraying speed is 6.3g/min, the material temperature is 28-35 ℃, the atomizing pressure is 0.2MPa, the sector pressure is 0.2MPa, the air outlet temperature is 35-38 ℃, and the negative pressure is-0.3 cmH₂O。

After coating, the core is dried in a coating pan at low pan speed for 8-15 minutes.

3. Intermediate control point

Preparing particles: granule moisture (required: LOD < 3%) and metformin content in the granules (required: 250 mg. + -. 5%).

Tabletting: the actual tablet weight was monitored (requirement: 350 mg. + -. 5%), the tablet hardness was monitored (requirement: >5 kgf); the actual content of metformin in the tablet core is determined (requirement: 250 mg. + -. 5%).

And (3) coating the enteric coating: the acid resistance and the release in a buffer solution of the metformin enteric-coated tablet are measured, and a VB12 layer is coated after the metformin enteric-coated tablet is qualified.

And (4) wrapping VB12 layer: and performing full detection according to a quality standard. The standard reaching rate is 99.8 percent.

Packaging in a PVC desiccant double-aluminum composite film and storing in a shade place.

Preparation example 2

The formulation and steps from step 2.1 to step 2.3, and the coating process in step 2.4 are the same as in preparation example 1. Except that the coating does not contain only VB12 but rather VB12 and VB 7.

2.4 layers of VB12+ VB7

1) VB12+ VB7 layer coating liquid formula

Each metformin tablet contains 26.5 mu g (+ -5%) of VB12 and 26.5 mu g (+ -5%) of VB7, and the VB12 and VB7 layers are wrapped in an amount which is 1.1 times of the formula because the medicine is lost, and the VB12 and VB7 raw materials need to be operated and stored in a dark place.

2) Preparing VB12+ VB7 layer liquid

The step is the same as 2 of the previous 2.4), except that VB12+ VB7 is added in the step (II).

3. Intermediate control point

Tabletting: the actual tablet weight was monitored (requirement: 350 mg. + -. 5%), the tablet hardness was monitored (requirement: >5 kgf);

the actual content of metformin in the tablet core is determined (requirement: 250 mg. + -. 5%).

And (3) coating the enteric coating: the acid resistance and the release in a buffer solution of the metformin enteric-coated tablet are measured, and a VB12 layer and a VB7 layer are coated after the metformin enteric-coated tablet is qualified.

And (3) wrapping VB12+ VB7 layer: and performing full detection according to a quality standard. The result reaches the standard rate of 99.7 percent.

Preparation example 3

The recipe and procedure of steps 2.1 to 2.4 are the same as in preparation 1 except that a VB7 layer was added to the VB12 layer.

2.5 layer VB7 bag

1) VB7 layer coating liquid formula

Each metformin tablet should contain 26.5 μ g (+ -5%) of VB7, and due to the loss of the medicine, the VB7 layer is coated in an amount which is 1.1 times of the amount of the formula, and the VB7 raw material needs to be operated and stored in a dark place.

2) Preparing VB7 layer liquid

The step is the same as 2 of the previous 2.4), except that VB7 is added in the step (c).

3) Layer VB7 package

The process conditions and equipment are the same as before.

And (4) wrapping VB7 layer: and performing full detection according to a quality standard. The standard reaching rate is 99.8 percent.

Preparation example 4

The tablets obtained in preparation example 1 above were coated with a light-screening agent:

1) sunscreen coating liquid formula

2) Preparing a sunscreen lotion

② titanium dioxide and Talc are added into 3-5 times (preferably 4 times) of water to carry out homogenization and dispersion for 10 minutes.

And thirdly, merging the second step into the first step, merging the rest water washing containers into the first step, and stirring the mixture evenly to obtain the opacifier layer liquid.

3) Coating with opacifier

The tablets obtained in preparation example 1 were taken out of the encapsulated PVC desiccant double aluminum composite film, put in a coating pan as described in preparation example 1, and coated with a light shielding layer using an infusion pump as described in preparation example 1. The inner diameter of the silica gel infusion tube is 3.1mm, the air inlet temperature is controlled to be 58-60 ℃, and the air volume is 100m³The pot rotating speed is 4-6rpm, the pump rotating speed is 7rpm, the average liquid spraying speed is 6.7g/min, the material temperature is 28-33 ℃, the atomizing pressure is 0.18MPa, the sector pressure is 0.2MPa, the air outlet temperature is 33-37 ℃, and the negative pressure is-0.3 cmH₂And O. After coating, the core is dried in a coating pan at low pan speed for 8-15 minutes.

Testing of content and Release

Investigation items and methods:

the content and the release degree are measured by a UV spectrophotometric method.

The release rate refers to the release rate in simulated gastric fluid (0.lmol/L hydrochloric acid).

1. The tablets of preparation 1 and 4 were compared and the results are given in the following table:

table 1 preparation examples 1 and 4 composite formulation data

	Preparation example 1	Preparation example 1	Preparation example 4	Preparation example 4
					Time of day	Content (%)	Degree of Release (%)	Content (%)	Degree of Release (%)
Day 0	99.3	0.1	99.8	0.1
					5 days	98.5	0.2	99.7	0.2
10 days	97.9	0.2	99.6	0.1
					15 days	97.2	0.1	99.6	0.2

2. As above, the respective measurements were carried out for the complex preparations of preparation examples 2 and 3

Table 2 preparation examples 2 and 3 composite formulation data

Claims

1. A preparation method of an oral compound preparation, the oral compound preparation is a metformin enteric-coated tablet coated by a vitamin B layer, the vitamin B and metformin are respectively released at different digestion parts step by step, the preparation method comprises the following steps:

1) firstly, a metformin tablet core is prepared from the following raw materials with the required weight per 1000 tablets:

2) then the isolation coating layer is prepared by the following raw materials by the required weight of each 1000 tablets:

3) then the enteric coating layer is prepared by the following raw materials with the required weight per 1000 tablets:

4) then the vitamin B layer is prepared by the following raw materials with the required weight per 1000 tablets:

2. The method for preparing an oral combination formulation of claim 1, wherein the binder of step 1) comprises PVPK30 and HPMCK4M, the disintegrant is MCC101, the filler is pregelatinized starch, and the lubricant comprises magnesium stearate and aerosil;

3. The method for preparing a compound preparation for oral administration of claim 1, further comprising coating a light-shielding layer containing a light-shielding agent component on the outside of the vitamin B layer.

4. The method for preparing an oral compound preparation according to claim 3, wherein the light-shielding layer comprises a chemical light-shielding layer and/or a physical light-shielding package; the light shading agent component of the chemical light shading layer is one or more than one of titanium dioxide, sunset yellow, carmine, indigo blue, iron oxide red and iron oxide yellow; the physical shading packaging product is any one of a PVC film, a PVC double-aluminum composite film or a PVC desiccant double-aluminum composite film.

5. The compound preparation for oral administration prepared by the preparation method according to claim 1, comprising a metformin core, an isolation coating layer, an enteric coating layer, and a vitamin B layer in this order from the inside to the outside.

6. The oral compound preparation of claim 5, wherein the mass ratio of the metformin tablet core to the sum of the isolation coating layer, the enteric coating layer and the vitamin B layer is 100: 13-19; the mass ratio of the isolation coating layer to the enteric coating layer to the vitamin B layer is 1: 3-6: 0.5-2.

7. The oral compound preparation of claim 5, wherein the mass percentage of the metformin to the whole oral compound preparation is 60-85%; the mass ratio of the metformin to the vitamin B is 6000-40000: 1.

8. the oral compound preparation of claim 5, which comprises a light-shielding layer containing a light-shielding agent component coated outside the vitamin B layer.