WO2008110070A1

WO2008110070A1 - Double-unit tablet comprising acid labile drug

Info

Publication number: WO2008110070A1
Application number: PCT/CN2008/000475
Authority: WO
Inventors: Jianhui Guo; Yaoru Lu; Haiying He
Original assignee: Shanghai Allist Pharmaceuticals, Inc.
Priority date: 2007-03-09
Filing date: 2008-03-10
Publication date: 2008-09-18
Also published as: CN101626755A; CN101626755B; CN101259108A

Abstract

A double-unit tablet of an acid labile active ingredient consists of two layers of layer A and layer B, wherein layer A comprises a basifying agent and a disintegrant, and it can disintegrate rapidly and release rapidly the basifying agent into gastric juice; layer B comprises an acid labile active ingredient, a basifying agent, a disintegrant and an excipient having retarding effect.

Description

Biunit tablet containing acid labile drugs

The present invention relates to the field of pharmaceutical preparations, and more particularly to a solid pharmaceutical preparation comprising an acid labile drug, particularly a proton pump inhibitor, and a preparation method and use thereof. technical background

H+ / K+ - triuretic adenosinease (Η" Κ ⁺ · - chymase) inhibitors, also known as proton pump inhibitors (PPIs), contain the following compounds: omeprazole, lansoprazole ( Lansoprazole ), pantoprazole, rabeprazole, tenatoprazole: pariprazole, leminoprazole and others. The compound may be used in a neutral form or in the form of an alkali salt, for example, in the form of a magnesium salt, a calcium salt, a sodium salt or a potassium salt, a single enantiomer of the compound or an alkali salt thereof, or a solvent may also be used. The form of the compound is used. - These drugs inhibit gastric acid secretion by irreversibly and specifically inhibiting the K+-ATPase enzyme system located on the secretory surface of the gastric parietal cells. These active substances are useful for inhibiting gastric acid secretion in mammals, especially humans. Therefore, it can be used to treat diseases associated with excessive gastric acid secretion, such as gastrinoma, gastric ulcer, duodenal ulcer, severe erosive esophagitis, and pathological gastric acid secretion. Other symptoms can also be used to relieve symptoms associated with other causes such as taking NSAIDs cause gastric mucosal damage.

PPIs are sensitive to degradation/transformation in acidic and neutral media and should be avoided when administered orally to the stability of gastric acid. In the prior art, oral dosage forms of such drugs are usually prepared by enteric pellets or tablets by enteric coating, i.e., coating with an enteric material. Technical solutions for such enteric coating formulations are described in Chinese Patent No. ZL96193594.4, ZL96190090.3, U.S. Patent No. 4,786,505, and European Patent No. EP0519365. In this embodiment, the formulation comprises a core of pellet or core, a buffer coating, and an enteric coating of the outer layer. In the core or core of the pellet, it is often necessary to coexist the drug with an alkalizing agent (or buffer) to maintain a high pH in a small environment and increase the stability of the PPIs. In order to avoid the influence of free carboxyl groups in the enteric material on the stability of the drug, a buffer coat layer having a certain thickness is required in the enteric coating layer. This means that in order to protect the stability of PPIs, multiple coatings are required. These all increase the formulation process and also increase the weight of the formulation, which is not beneficial for the patient. Some operations in the preparation process, such as high temperature operation during coating and collision of particles, deformation of the coated enteric coated particles during tableting, or uneven coating thickness, may also lead to drug expectations. Unstable. A formulation that avoids the tablet compression process, such as a suspension, as specifically A US-listed omeprazole dry suspension consisting of omeprazole, sodium bicarbonate and magnesium hydroxide, and excipients. This preparation still needs to be enteric coated; and therefore it is bulky and needs to be dispersed before taking it, so it is inconvenient to take it; in addition, as a dry powder preparation, its packaging requirements are relatively high. A similar prior art is also a two-layer chewable tablet as described in WO2004066924, the oral rapid disintegration preparation described in CN01820259.4.

The above PPIs preparations are not all of the oral preparations, and thus cause inconvenience in the manner of administration. It would be beneficial to overcome stability and deficiencies in the manner of administration if a holistic oral tablet that does not require an enteric coating to ensure stability of the PPIs during preparation and dispersion in the body is provided. A two-part tablet as described in the prior art, such as CN02817249.3, which comprises an enteric-free inner core comprising (a) a proton pump inhibitor and an optional primary essential buffer, and b) coating the outer layer of the inner core comprising a primary essential buffer and an optional secondary essential buffer. The main essential buffers independently include: sodium hydrogencarbonate, sodium sesquicarbonate, etc., and preferably sodium hydrogencarbonate.

The chip in the PPIs of the examples mentioned in the specification of the patent application, the nucleus was uniformly coated with 975 mg of sodium hydrogencarbonate to form a layer of an external protective coating of sodium hydrogencarbonate. Both the core and the outer cover are prepared using standard adhesives and other excipients to form a pharmaceutically acceptable finished tablet.

As mentioned on page 51 of this patent application specification, 750 mg of sodium bicarbonate and 10 mg of omeprazole powder form an inner core, and 10 mg of omeprazole casing particles mixed with known binders and excipients form an outer core. After the entire tablet was taken, the tablet dissolved. The inner core is dispersed in the stomach and absorbed to achieve an immediate therapeutic effect. The program still contains a casing section.

In the 77th page of the patent application specification, the buffer disintegrates and reaches the solution at a rate exceeding the PPIs, thereby providing the necessary p _{H to} protect the PPIs before they dissolve and react with the acid in the environment. Alternatively, the tablets or capsules can be made into an interior having a buffer-containing exterior and a mixture comprising PPIs or PPIs and a buffer. These production methods are designed to create a stable environment for PPIs during their residence time.

As can be seen from the above disclosure, the technical solution provides for the prevention of degradation of PPIs by using a fast reacting buffer such as sodium bicarbonate and a slow reacting buffer such as magnesium oxide or magnesium hydroxide. One solution is: the inner layer of PPIs and sodium bicarbonate, and the outer layer of magnesium hydroxide xerogel or magnesia with a suitable disintegrant so that the magnesium oxide will rapidly disintegrate in the stomach. Alternatively, the inner layer may comprise the magnesium buffer and the outer layer contains PPIs and sodium bicarbonate.

It can be seen that in the technical solution disclosed in the patent application, the solution is limited to preventing the degradation of PPIs by selecting the kind of buffer, such as the buffer neutralization speed and the amount of the buffer, that is, basically relying on the buffer and the gastric juice. Neutralization speed. The protective effect of this method is often unreliable, such as tablets containing a variety of excipients, The granules are exposed from the excipients and the PPIs may be exposed to gastric juice and degraded prior to neutralization with gastric juice. Another solution proposed in the patent application is to prepare a complex tablet having an inner layer and an outer layer. The technical solution is also unreliable for the protection of PPIs. According to the invention, PPIs may not raise the pH of the gastric juice after the outer layer disintegrates. When it is released, it may be exposed to gastric juice and degraded. In addition, such complex internal and external two-part tablets have certain difficulties in industrial production.

The two-unit tablet of the present invention overcomes the unreliability of the protection of PPIs, and starts from the excipients, and strictly and precisely controls the release time of the buffer (i.e., the alkalizing agent in the present invention) and PPIs, thereby ensuring The PPIs are released after the pH is raised to provide a safe protection; on the other hand, the two-unit tablet of the present invention is very suitable for industrial production, and now has similar forms of product production and sales; meanwhile, the present invention also It overcomes the shortcomings of the so-called internal and external double-layered complex tablets that are difficult to industrialize. Summary of the invention

The present invention provides an oral tablet containing an acid labile active ingredient, which avoids the complicated process of using an enteric material and the multiple coatings necessary thereby, by controlling the release sequence of the alkalizing agent and the active ingredient, thereby It ensures the stability of the acid labile active ingredient.

The present invention provides an oral tablet which is particularly suitable for PPIs, which can rapidly neutralize gastric acid after oral administration, release active ingredients, and provide sustained acid suppression.

The present invention achieves the above object by providing a two-unit tablet composed of two sheets of A and B. Among them, the sheet A as an immediate release portion contains a sufficient amount of alkalizing agent and a high-performance disintegrating agent to allow it to rapidly disintegrate and release the alkalizing agent after entering the stomach; the sheet B specifically contains a hindrance The cleavage excipient (also referred to as "blocking carrier" in the present invention) and the high performance disintegrant, the acid labile active ingredient is dispersed in the retardation carrier. The combination of the retardation carrier and the disintegrant allows the acid-labile active ingredient to be released in the alkalizing agent in the layer A and neutralized by the gastric acid, thereby preventing the stability of the acid-labile active ingredient while not being Will cause absorption delay. The inventors have conducted intensive studies and found that by selecting an appropriate excipient, the two components can be strictly and sequentially released in a short period of time.

The acid labile active ingredient in the bi unit tablet of the present invention may be selected from the above-mentioned PPIs, specifically including omeprazole, pantoprazole, lansoprazole, rabeprazole, tetoprazole, pa Liraazole, lanololazole and its pharmacologically suitable racemates, basic salt forms, or one of their individual enantiomers or its basic salt form, or in the form of a solvate Particularly preferred are pantoprazole sodium sesquihydrate, pantoprazole magnesium dihydrate, olaprazole magnesium, omeprazole and esomemagazole. The amount of the active ingredient contained in the unit preparation of the two-unit tablet of the present invention is now The dosage of the clinically used preparation is consistent, such as omeprazole dose of 10mg, 20mg, 40mg, pantoprazole dose of 20mg, 40mg, lansoprazole dose of 15mg, 30mg, rabeprazole dose of 20mg, or Other effective doses clinically proven.

The alkalizing agent contained in the bi unit tablet of the present invention may be selected from, but not limited to, an electrolyte containing cationic sodium, potassium, calcium, magnesium, aluminum or cesium, such as sodium hydrogencarbonate, potassium hydrogencarbonate, magnesium lactate, magnesium carbonate. , magnesium silicate, magnesium gluconate and other magnesium salts, aluminum hydroxide / sodium bicarbonate coprecipitate, basic amino acids, and also include magnesium oxide, magnesium hydroxide, sodium citrate, sodium acetate, sodium carbonate, and more Sodium, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium chloride, hydrogen Calcium oxide, calcium lactate, calcium carbonate, calcium bicarbonate and other calcium salts. These alkali compounds may be suitably used in the present invention either singly or in combination. It should be noted, however, that basophils which cause gastrointestinal mucosal irritation to produce too high a pH value are not suitable for use alone.

The retardation carrier contained in the sheet B in the bi unit tablet of the present invention is selected from the group consisting of pH-sensitive polymers and carrier materials having water swelling properties.

The specific details of the invention are as follows:

Layer A composition

Sheet A contains an alkalizing agent and a disintegrant, and the necessary excipients. After a plurality of screening combinations, the inventors obtained an ideal combination of an alkalizing agent, a disintegrating agent and other excipients in the sheet A to disintegrate in an artificial gastric juice within 3 minutes to release an alkalizing agent.

The amount of the alkalizing agent in the sheet A is such as to neutralize the already existing gastric acid, and at the same time, it is desirable to have a faster neutralization speed. In one embodiment, the alkalizing agent in the sheet A is selected from the group consisting of sodium hydrogencarbonate, magnesium hydroxide and magnesium oxide. After neutralization of sodium bicarbonate with an equivalent amount of gastric acid (hydrochloric acid), the resulting pH is the pKa of its conjugate acid (carbonic acid), about 6.14 or greater, and magnesium hydroxide or magnesium oxide provides a sustained neutralization effect. , thus providing a safe pH environment for PPIs. These alkalizing agents are used in an amount to neutralize about 4 to 10 moles of hydrochloric acid. In the unit preparation, the amount of sodium bicarbonate is 350~800 mgo

Sheet A also requires rapid disintegration after entering the body, so the use of excellent disintegrants, such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, The low-substituted hydroxypropylcellulose is used in an amount of 4% to 10% by weight based on the total weight of the layer A, and its effect is to prevent the disintegration time of the layer A in 150 ml of artificial gastric juice for not more than 3 minutes. One embodiment of the composition of the sheet layer A of the present invention is: using a combination of sodium hydrogencarbonate, magnesium hydroxide and magnesium oxide as an alkalizing agent, using crosslinked polyvinylpyrrolidone as a disintegrating agent, and adding a necessary filler, Excipients such as adhesives and lubricants. In the sheet A, the total amount of the alkalizing agent is required to neutralize about 4 to 10 mmol of hydrochloric acid. The cross-linked polyvinylpyrrolidone is present in an amount of from 4% to 8% by weight based on the weight of the sheet A. The filler may be selected from one or more of microcrystalline cellulose, mannitol, starch, pregelatinized starch, dextrin, sucrose, lactose, calcium sulfate, calcium phosphate, and the binder may be selected from the group consisting of microcrystalline cellulose, mannitol, starch, pregelatinized starch, sucrose, lactose, calcium sulfate, calcium phosphate, and the like. One or more of povidone, hypromellose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, the lubricant may be selected from the group consisting of stearic acid, calcium stearate, One or more of magnesium stearate, talc, magnesium decyl sulfonate, polyethylene glycol, the surfactant may be selected from the group consisting of a Tween surfactant and sodium dodecyl sulfonate Wait.

Sodium bicarbonate can also be used alone in sheet A in an amount to neutralize about 4 to 10 moles of hydrochloric acid.

Layer B composition

Sheet B is a drug-containing layer comprising an acid labile active ingredient, an alkalizing agent, a disintegrant, and an excipient having a retarding action, and other excipients necessary; wherein, acid labile activity The ingredients are dispersed in a carrier having a retarding effect for the purpose of appropriately delaying the release. However, it should be clear that this temporary delay is within 10 minutes and does not cause delays in the release and absorption of active ingredients.

The active ingredient in sheet B is co-present with the basifying agent, and an alternative basifying agent such as the type of basifying agent mentioned in sheet A is used. In the preparation unit for one administration, the sum of the amount of the alkalizing agent in the sheet B and the amount of the alkalizing agent in the sheet A should be able to neutralize hydrochloric acid of 4 to 45 mEq. The type/combination of the alkalizing agent and its amount are adjusted according to the stability of the active ingredient to pH. The purpose is to maintain the pH of the gastric juice at least +1 of the active ingredient during the stay of the drug in the stomach to prevent degradation. .

In the present invention, the retardation carrier is selected from the group consisting of pH-sensitive polymers and carrier materials having water swelling properties. As is well known to those skilled in the art, other materials having a retarding effect are also applicable to the object of the present invention, and are also included in the technical solution of the present invention.

The water-swellable carrier material is, for example, a highly swellable polymer when contacted with water or an aqueous medium, a polymer that forms a gel in contact with water or an aqueous medium, a polymer that contacts water or an aqueous medium having swelling and gelling properties. , hydrogels, sugar-based substances, protein substances or mixtures thereof, specifically:

a highly swellable polymer in contact with water or an aqueous medium such as gastric contents, selected from the group consisting of sodium carboxymethylcellulose, crosslinked hydroxypropylcellulose, high molecular weight hypromellose, carboxymethylamide, potassium methacrylate Divinylbenzene copolymer, polymethyl methacrylate, crosslinked PVP, high molecular weight polyvinyl alcohol, and the like.

a polymer that forms a gel when exposed to water or an aqueous medium such as stomach contents, selected from methyl cellulose, carboxymethyl fibers , low molecular weight hypromellose, low molecular weight polyvinyl alcohol, polyoxyethylene alcohol, non-crosslinked polyvinylpyrrolidone, xanthan gum, and the like.

A polymer capable of simultaneously expanding and forming a gel upon contact with water or an aqueous medium such as a stomach contents, selected from the group consisting of medium and low viscosity hypromellose and medium and low viscosity polyvinyl alcohol.

Other known polymers with delayed drug release may also be used, including hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, sugar-based materials such as tragacanth, guar gum, agar, pectin. , carrageenan, soluble and insoluble alginate, carboxypolyethylene, casein, zein, etc., as well as proteinaceous materials such as gelatin.

These materials can be used singly or in combination. Preferred are medium to low viscosity hypromellose, methyl cellulose, carboxymethyl cellulose, medium and low viscosity polyvinyl alcohol, non-crosslinked polyvinylpyrrolidone, xanthan gum and the like.

In the layer B, the above-mentioned carrier material and/or disintegrant having a retarding effect is selected to achieve precise control of the release time and speed of the active ingredient, which is neither instantaneous and rapid release, nor does it cause undesired delay or slowness. release. A carrier material having water swelling properties is preferred. For the purpose of exemplification, the selection and the range of use of the retardation carrier and the disintegrant are exemplified below.

(1) Hydroxypropyl methylcellulose with a viscosity of 3 to 50 cP, such as commercially available METHOCEL.E3 PREMIUM, METHOCEL E5 PREMIUM, METHOCEL E6 PREMIUM, PHARMACOAT 603, PHARMACOAT 606, PHARMACOAT 615, etc. 8% to 30% by weight; and crosslinked polyvinylpyrrolidone (PVPP XL) as a disintegrant in an amount of 6% to 8% based on the total weight of the sheet B.

(2) Sodium alginate with a viscosity of 20 ~ 400 cP, such as sodium alginate with a viscosity of 20 ~ 400 cP, the amount is 8% ~ 30% of the weight of the layer B, PVPP XL as a disintegrant, the amount is a layer 6% to 10% of the total weight of B.

(3) The viscosity is 5 to 130 cP sodium carboxymethylcellulose, and the amount is 8% to 30% by weight of the layer B. Low-substituted hypromellose is selected as the disintegrant in an amount of from 8% to 10% by weight of the sheet B.

(4) Methylcellulose with a viscosity of 5 to 15 cP, in an amount of 8% to 30% by weight of the layer B. The croscarmellose sodium is used as a disintegrant in an amount of from 5 % to 10% by weight based on the weight of the sheet B.

(5) Xanthan gum with a particle size of 200 mesh or more, in an amount of 5% to 20% by weight of the layer B. The croscarmellose sodium is used as a disintegrant in an amount of 6% to 10% by weight of the sheet B.

The combination of the above-mentioned retardation carrier and disintegration is a main component of the sheet B of the present invention, and when it is compressed into a tablet, it is necessary to add other excipients such as a filler binder, a lubricant, and the like. Surfactants, etc. The filler may be selected from one or more of microcrystalline cellulose, mannitol, starch, pregelatinized starch, dextrin, sucrose, lactose, calcium sulfate, calcium phosphate, and the binder may be selected from the group consisting of microcrystalline cellulose, mannitol, starch, lactose, calcium sulfate, calcium phosphate, and the like. Povidone, hypromellose, sodium carboxymethylcellulose, A One or more of cellulose, ethyl cellulose, which may be selected from the group consisting of stearic acid, calcium stearate, magnesium stearate, talc, magnesium decyl sulfonate, polyethylene One or more of the diols, and the surfactant may be selected from the group consisting of a Tween-based surfactant and sodium dodecylsulfonate.

Preparation of two-unit tablets

The preparation method of the two-unit tablet of the invention is:

(1) pulverizing and mixing the material of the sheet layer A as described above, including an alkalizing agent, a disintegrant, and other necessary excipients; or another preparation scheme: an alkalizing agent, a disintegrating agent, and some other The granules were granulated, dried, and mixed with the remaining excipients to obtain a sheet A material.

(2) the material of the layer B as described above includes an active ingredient, an alkalizing agent, a disintegrating agent and other necessary excipients, pulverized, sieved, and mixed; or another preparation scheme, the active ingredient, alkalized The agent, and a part of other excipients such as a filler, a binder, mixed with an excipient having a retarding effect, granulated, dried, sized, and mixed with the remaining excipients to obtain a sheet B material.

(3) The above-mentioned sheet A material and sheet B material are pressed into a two-layer sheet by a conventional two-layer sheet pressing method, or the sheet B material containing the active ingredient may be first tableted to obtain a core sheet B, and then a sheet is obtained. The layer A material completely encloses the core B, and the tablet is packaged.

In the above preparation method, the method of dispersing the active ingredient in the carrier material having the retardation effect in the sheet B may also be carried out by: pulverizing the acid labile active ingredient and the carrier material separately, and sieving, Mix, with or without other ingredients, granulate, dry; or use fluidized bed granulation.

Biunit tablets containing PPIs

The technical solution and the effect of the two-unit tablet using PPIs as the active ingredient according to the above invention are illustrated by the following examples: Layer A: sodium hydrogencarbonate 350 to 800 mg, magnesium hydroxide 250 to 350 mg, heavy magnesium oxide 20 ~ 50 mg, filler 150 ~ 200 mg, disintegrant 50 ~ 100 mg, PVP K29/30 5 ~ 20 mg, add appropriate amount of magnesium stearate, mix evenly, get sheet A material. Alternatively, some materials such as magnesium hydroxide and heavy magnesium oxide may be granulated.

Sheet B: Dissolve 10 to 20 mg of PVP k29/32 and about 5 mg of sodium bicarbonate in an appropriate amount of water, with a unit effective dose of PPIs, sodium bicarbonate 95 to 345 mg, heavy magnesium oxide 20 to 70 mg, filler 30 to 40 mg, in a fluidized bed. The obtained granules are mixed with 20 to 40 mg of a disintegrant, and 60 to 140 mg of a water-swellable polymer material and an appropriate amount of a lubricant to obtain a sheet B material.

Preparation: Mix the two parts of the layer A and the sheet B separately, apply the two-layer tablet press, and press B first. In part, the A part is further compressed to obtain a PPIs bilayer tablet. The preferred preparation form is: a sheet thickness of about 9.0 mm and a tablet weight of 1000 mg to 2000 mg.

The prepared PPIs tablets were tested for dissolution and acid resistance as follows:

Dissolution test using dissolution test (2005 version of the Pharmacopoeia Appendix XC third method) device, with acid solution (take sodium chloride 2.0 g, add hydrochloric acid 7.0 ml, add water to dissolve and dilute to 1000 ml, pH value 1.2) 150 ml For solvent, the rotation speed is 100 rpm, and operate according to law. Start the time of putting the double-layer tablet. At 45 minutes, take the appropriate amount of the solution, filter, and accurately measure 0.5 ml with pHIO aqueous solution (add 1000 ml of 1 mol/1 sodium hydroxide in 1000 ml of water, then use 1 mol/1 Dilute the sodium hydroxide or dilute acetic acid solution to a pH of 10.00 ± 0.10) to 10 ml, determine the component content by high performance liquid chromatography, and calculate the drug dissolution.

Determination of acid resistance Take this product, using the dissolution method (2005 version of the Pharmacopoeia Appendix XC third method) device, with 150 ml of acid solution (take sodium chloride 2.0g, add hydrochloric acid 7.0ml, add water to dissolve and dilute to 1000ml, pH A value of 1.2) is the dissolution medium. The rotation speed is 100 rpm, and the time is started when the double-layer tablet is put into use. After 120 minutes, the suspension in the dissolution cup is completely transferred to a 250 ml brown volumetric flask, and about 90 ml of ethanol alkali solution (Ig NaOH) is used. Dissolve in 10 ml of water and dilute to 1000 ml with ethanol. Rinse the vessel. The rinse is transferred to a 250 ml brown vial and sonicated for 10 min. Add water: The solution of ethanol alkali solution (5: 3) is adjusted to the mark, shake well, centrifuge, filter, and accurately take 4 ml of the filtrate into a 10 ml brown volumetric flask, dilute to the mark with pHIO aqueous solution, shake well. The component content was determined by high performance liquid chromatography to evaluate the acid resistance of the formulation.

The dissolution and acid resistance of the two-unit tablet of the present invention were measured, and as a result, the dissolution was 90% to 104%; under the conditions of the acid resistance test, the degradation of the active ingredient was remarkably lower than that of the comparative example. It is indicated that the release of the acid labile active ingredient of the present invention can be well controlled to better ensure the stability of the acid labile active ingredient.

The above schemes are given for the purpose of exemplification and do not constitute a limitation on the selection of the active ingredient of the present invention, the formulation of the formulation, the preparation method, the form of the preparation, and the performance parameters of the preparation. For other acid labile drugs, those skilled in the art can calculate the amount of the alkali compound in a similar manner, and according to the properties of the active ingredient and the carrier having the retardation effect, after a simple experiment, the screening can be reasonably combined. Also included within the scope of the dual unit tablet of the present invention.

As used herein, the term "PPIs", also known as "proton pump inhibitors", refers to a benzimidazole compound that inhibits gastric acid secretion by a K+-ATPase system (proton pump) that irreversibly and specifically inhibits the secretory surface of cells in the parietal wall. . The PPIs of the present invention include all substituted benzimidazole PPIs, their salts, esters, amides, enantiomers, racemates, prodrugs, derivatives, etc., and are not limited to those compounds exemplified for illustration. . The terms "alkaline" and "basifying agent" as used herein have the same meaning and refer to a basic substance capable of neutralizing reaction with hydrochloric acid.

The term "unit preparation" as used herein, refers to a preparation comprising an effective dose administered once, usually in the form of a separate preparation, such as a single tablet, which may contain the active ingredient as 10 mg, 20 mg, 40 mg of omeprazole, or 20 mg, 40 mg of pantoprazole, or 15 mg, 30 mg of lansoprazole, or 20 mg of rabeprazole.

The term "effective amount" as used herein means an amount of active ingredient which, in accordance with the considerations known in the art, is effective to achieve pharmacological effects or therapeutic amelioration without excessive adverse side effects, such as PPIs from 2 mg/day to 300 mg/day. .

detailed description

The present invention will be further described in detail below with reference to the embodiments. The examples are given by way of illustration and not as a limitation of the invention.

Example 1 Pantoprazole sodium double-layer tablet

The prescription is as follows:

Preparation: PVP k29/32 and 3 g sodium bicarbonate in layer B were dissolved in 200 ml of water, with pantoprazole sodium 44.7 g, sodium hydrogencarbonate 117 g, heavy magnesium oxide 20 g and mannitol 35 g Fluidized bed made of granules. The obtained granules were mixed with 20 g of PVPP XL 120 g pharmcoat 603 and an appropriate amount of magnesium stearate to obtain a sheet B material. Slice A The ingredients are comminuted and mixed. Using a two-layer tablet press, the B part is first pressed, and then the A part is pressed to obtain 1000 pieces of pantoprazole sodium double-layer tablet having a sheet thickness of about 9.0 mm.

Effect: The obtained two-layer sheet was subjected to measurement of dissolution and acid resistance, and the measurement method was as described above. The dissolution was measured to be 96.6%.

Comparative Example 1: The pharm _COa t 603 in the above-mentioned sheet B was removed, and the two-layer sheet was pressed as described above. The tablet of Example 1 and the tablet of this comparative example were subjected to acid resistance. The test method was as described above. The results are as follows:

Example 2 Omeprazole double layer sheet

The prescription is as follows:

Preparation: The components in the layer A and the sheet B were separately pulverized and mixed. Using a two-layer tablet press, the B part is first pressed, and then the A part is pressed to obtain 1000 omeprazole double-layer tablets having a sheet thickness of about 9.0 mm.

Effect: The obtained two-layer sheet was subjected to measurement of dissolution and acid resistance, and the measurement method was as described above. The dissolution was measured to be 101.2%. Comparative Example 2: The sodium alginate in the above sheet B was removed, and the two-layer sheet was pressed as described above. The tablet of Example 2 and the tablet of the comparative example were subjected to acid resistance measurement, and the test method was as described above. The results are as follows:

Example 3 Lansoprazole package chip

The prescription is as follows:

Preparation: PVP k29/32 and 5 g sodium bicarbonate in sheet B were dissolved in 200 ml of water, and lansoprazole 30 g, sodium bicarbonate 345 g, heavy magnesium oxide 50 g and starch 30 g were prepared by wet method. The granules are granulated, dried at 50 to 60 ° C, and whole. The obtained granules were mixed with 35 g of sodium carboxymethyl starch, 60 g of sodium carboxymethylcellulose, and an appropriate amount of magnesium stearate to obtain a sheet B material. The components in the layer A are pulverized and mixed, and the two-layer tablet press is applied. First, the part B is pressed to obtain the core B, and then the core B is coated with the sheet A material to obtain 1000 lansoprazole double-layer chips. The tablet has a thickness of about 10.0 mm.

Effect: The prepared double-layered chip was subjected to measurement of dissolution and acid resistance, and the measurement method was as described above. The measured dissolution was 94.4%.

Comparative Example 3: The sodium carboxymethylcellulose in the above-mentioned sheet B was removed, and the two-layer sheet was pressed as described above. The tablet of Example 3 and the tablet of the comparative example were subjected to acid resistance measurement, and the test method was as described above. The results are as follows: Sample acid resistance test results (% drug degradation, unit: %)

Source Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Comparative Example 3 8.52 7.45 6.53 8.12 7.25 6.68 Example 3 2.99 3.64 3.46 3.22 3.46 3.48 Example 4 Pantoprazole Double Layer

The prescription is as follows:

Preparation: PVP k29/32 and 5 g sodium bicarbonate in layer B were dissolved in 200 ml of water, and pantoprazole, sodium hydrogencarbonate 95 g, heavy magnesium oxide and lactose were prepared by fluidized bed granules. The obtained granules were mixed with 30 g of croscarmellose sodium, 90 g of methylcellulose and an appropriate amount of magnesium stearate to obtain a sheet B material. The components in the layer A were pulverized and mixed, and a two-layer tablet press was used. The portion B was first pressed, and the portion A was pressed to obtain 1000 sheets of pantoprazole double-layer tablets having a thickness of about 9.0 mm.

Effect: The obtained two-layer sheet was subjected to measurement of dissolution and acid resistance, and the measurement method was as described above. The dissolution was measured to be 96.7%.

Comparative Example 4: The methyl cellulose in the above sheet B was removed, and the two-layer sheet was pressed as described above. The tablet of Example 4 and the tablet of the comparative example were subjected to acid resistance measurement, and the test method was as described above. The results are as follows:

Sample Acid resistance test results (% drug degradation, unit: %)

Source Sample 1 Sample 2 Sample 3 - Sample 4 Sample 5 Sample 6 Comparative Example 4 8.55 10.24 8.57 9.25 8.75 10.46 Example 4 5.48 5.95 6.00 6.02 5.64 5.97 Example 5 Rabeprazole double layer sheet

The prescription is as follows:

Preparation: The components in the layer A and the sheet B were separately pulverized and mixed. Using a two-layer tablet press, the B part is first pressed, and then the A part is pressed to obtain 1000 pieces of rabeprazole double-layer tablet having a sheet thickness of about 9.0 mm.

Effect: The obtained two-layer sheet was subjected to measurement of dissolution and acid resistance, and the measurement method was as described above. The dissolution was measured to be 101.2%.

Comparative Example 5: The sodium carboxymethylcellulose in the above-mentioned sheet B was removed, and the two-layer sheet was pressed as described above. The tablet of Example 5 and the tablet of the comparative example were subjected to acid resistance measurement, and the test method was as described above. The results are as follows:

Sample Acid resistance test results (% drug degradation, unit: %)

Source Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Sample 6 Comparative Example 5 9.66 7.87 8.87 7.65 8.55 7.45 Example 5 3.10 3.22 2.96 3.87 4.02 3.65

Claims

Rights request

A two-unit tablet comprising two layers of a sheet A and a sheet B, the sheet A comprising an alkalizing agent, a disintegrant and other excipients; the sheet B comprising an acid-labile active ingredient , an alkalizing agent, a disintegrating agent, and a carrier having a retarding effect on the release of the active ingredient, and other excipients; wherein the acid-labile active ingredient is dispersed in a carrier having a retarding effect; said sheet A And the total amount of the alkalizing agent of the sheet B can neutralize hydrochloric acid of 4 to 45 mEq.

The two-unit tablet according to claim 1, wherein the alkalizing agent in the sheet A or the sheet B is selected from the group consisting of sodium hydrogencarbonate, potassium hydrogencarbonate, magnesium hydroxide and magnesium oxide. Kind.

The two-unit tablet according to claim 2, wherein the alkalizing agent in the sheet A is composed of sodium hydrogencarbonate, magnesium oxide and magnesium hydroxide in an amount capable of neutralizing hydrochloric acid of 4 to 10 mmol; The alkalizing agent in the sheet B is sodium hydrogencarbonate and magnesium oxide.

The two-unit tablet according to claim 1, wherein the disintegrating agent contained in the sheet A is selected from the group consisting of croscarmellose sodium, crosslinked polyvinylpyrrolidone, and carboxymethyl starch. Sodium and low-substituted hydroxypropylcellulose are used in an amount of from 4% to 10% by weight based on the total weight of the sheet A.

The two-unit tablet according to claim 1, wherein the carrier having a retardation contained in the sheet B is selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, and sodium carboxymethylcellulose. , methylcellulose and xanthan gum, the amount of which is 5% to 30% by weight of the layer B; the layer B contains a disintegrant selected from the group consisting of crospovidone, sodium carboxymethyl starch, and crosslinked carboxymethyl The base cellulose sodium and the low-substituted hypromellose are used in an amount of 5% to 10% by weight of the sheet B.

The two-unit tablet according to claim 5, wherein the carrier having a retardation contained in the sheet B is selected from hydroxypropylmethylcellulose having a viscosity of from 3 to 50 cP. The amount is 8% to 30% by weight of the sheet B.

The two-unit tablet according to claim 5, wherein the carrier containing the retardation contained in the sheet B is selected from the group consisting of sodium alginate having a viscosity of 20 to 400 cP, and the amount thereof is a sheet layer. B weight 8% ~ 30%.

The two-unit tablet according to claim 5, wherein the carrier having a retardation contained in the sheet B is selected from the group consisting of sodium carboxymethyl cellulose having a viscosity of 5 to 130 cP. It is 8% to 30% of the weight of the sheet B.

The two-unit tablet according to claim 5, wherein the carrier having a retardation contained in the sheet B is selected from methyl cellulose having a viscosity of 5 to 15 cP, and the amount thereof is a tablet. Layer B weighs 8% to 30%.

The two-unit tablet according to claim 5, wherein the sheet B contains a retardation The carrier of the action is selected from the group consisting of 100 to 400 mesh xanthan gum in an amount of 5% to 20% by weight of the layer B.

The two-unit tablet according to claim 1, wherein the sheet A and the sheet B comprise other excipients including one of a filler, a binder, a lubricant, and a surfactant. Or one or more; the filler is selected from one or more of microcrystalline cellulose, mannitol, starch, pregelatinized starch, dextrin, sucrose, lactose, calcium sulfate, and calcium phosphate; The agent is selected from one or more of povidone, hypromellose, sodium carboxymethylcellulose, methylcellulose and ethylcellulose, the lubricant being selected from the group consisting of stearic acid and stearic acid. One or more of calcium, magnesium stearate, talc, magnesium lauryl sulfonate and polyethylene glycol, the surfactant being selected from the group consisting of Tween surfactants and dodecyl sulfonic acid sodium.

The two-unit tablet according to claim 1, wherein the acid-labile active ingredient contained in the sheet B is selected from the group consisting of omeprazole, pantoprazole, lansoprazole and thunder Betaprazole and its pharmacologically suitable racemates, basic salt forms, and one of their individual enantiomers or its basic salt forms, and solvated forms, the amount of which is clinically effective dose.

13. The two-unit tablet according to claim 1, wherein the total weight of the two-unit tablet is from 1000 to 2000 mg.

A method of producing a two-unit tablet according to any one of claims 1 to 13, characterized in that the method comprises the steps of:

(1) Preparation of the sheet A: pulverizing and mixing the alkalizing agent in the sheet A with the disintegrant and other excipients; or granulating the alkalizing agent in a solution of PVP K29/30 in ethanol, after drying, Mixing with the remaining excipients to obtain the material of the layer A;

(2) Preparation of sheet B: The active ingredient, the alkalizing agent, the disintegrant, the carrier component having water swelling property and other excipients in the sheet B are pulverized, sieved, mixed, or granulated into a part of the material. , drying, whole grain, to obtain the material of the layer B;

(3) Preparation of two-unit tablet: The above-mentioned sheet A material and sheet B material are pressed into a two-unit tablet by a conventional two-layer tablet pressing method; or the sheet B material containing the active ingredient may be first tableted. The core B is obtained, and the core B is completely encapsulated by the sheet A material, and the tablet is obtained into a two-unit tablet.

15. Use of a two unit tablet according to any of claims 1 to 13 for the treatment of hyperacidosis.