CN1732952B - A compound dispersible tablet for treating hypertension - Google Patents

Abstract

The invention relates to a pharmaceutical oral preparation containing valsartan and hydrochlorothiazide, in particular to a dispersible tablet dosage form for enhancing the beneficial effects of valsartan and hydrochlorothiazide. It has a rapid onset of action and enhances the beneficial effects of the active ingredient and can be administered easily without any discomfort.

Description

A compound dispersible tablet for treating hypertension

technical field

The present invention relates to pharmaceutical oral formulations comprising valsartan and hydrochlorothiazide, in particular to a dispersible tablet form for enhancing the beneficial effects of valsartan and hydrochlorothiazide.

Background technique

Valsartan is an angiotensin II (Angiotensin II) receptor inhibitor, which can inhibit the conversion of Ang I to Ang II, and specifically antagonizes the angiotensin converting enzyme 1 receptor (AT1), and its antagonism to AT1 is 500 times greater than that of AT2 , by selectively blocking the combination of Ang II and AT1 receptors, inhibiting vasoconstriction and the release of aldosterone, resulting in antihypertensive effects. Hydrochlorothiazide (hydrochlorothiazide, HCTZ) is a traditional antihypertensive drug and belongs to the middle-effect diuretic. Acts on the distal renal tubule to activate the renin-angiotensin system (RAS). The combined application of the two can make blood pressure more effectively controlled; compared with the single preparation, the dosage of each drug is reduced, and the incidence of adverse drug reactions is also reduced accordingly. Patients with lower serum potassium; more convenient for patients to take, improve patient compliance. Therefore, the compound preparation of valsartan and hydrochlorothiazide has increasingly become the drug of choice for hypertensive patients due to its long action time, good curative effect, and many advantages such as small side effects. Oral administration and absorption through the gastrointestinal tract is the preferred route of administration, and currently there are oral dosage forms such as tablets and capsules.

After oral administration of valsartan and hydrochlorothiazide, the blood drug concentration reaches the peak in about 2-4 hours, which is mainly due to the inherent properties of the above two main ingredients. Those skilled in the art are well aware that solid preparations need to go through the process of disintegration, dissolution, and absorption, which is very unfavorable for the effectiveness of poorly soluble drugs, so it is difficult for ordinary preparations to meet the urgent needs of hypertensive patients to relieve symptoms as soon as possible. Therefore, it has become a technical problem for those skilled in the art to develop oral formulations of valsartan and hydrochlorothiazide that can rapidly exert a therapeutic effect and are suitable for use by a wider population.

Therefore, it is easy for those skilled in the art to understand, and it is also eager to develop a compound quick-acting preparation of valsartan and hydrochlorothiazide, which can act rapidly and enhance the beneficial effect of the active ingredient, and can be easily, without any discomfort and any concerns. medication. Using strong fluid excipients for direct compression of dry powder or dry granulation technology can directly realize the preparation, but on the one hand, it will increase the production cost. On the other hand, this technology is not as good as wet granulation technology. Universal, not conducive to general use on a wider scale.

Dispersible tablet form seems to be a technical solution to the above problems. However, so far, no one has provided a scientific basis for the development of dosage forms of valsartan and hydrochlorothiazide.

Contents of the invention

The object of the present invention is to provide a dispersible tablet comprising therapeutically effective doses of valsartan and hydrochlorothiazide as active ingredients.

As mentioned above, both valsartan and hydrochlorothiazide are poorly soluble drugs. Therefore, it is first necessary to provide a composition suitable for preparing dispersible tablets, which should be stable without reducing the bioavailability of the active ingredient, and even significantly increase the bioavailability of the active ingredient.

In the pilot test, the inventor prepared the dispersible tablets of valsartan and hydrochlorothiazide according to the prescription for preparing dispersible tablets often used by those skilled in the art. In the research, it was found that the most commonly used lactose was not conducive to improving the stability of the preparation. On the one hand, due to the crystal water contained in lactose, the main ingredient is in an unstable state, and it is easy to absorb moisture during the preparation process to further interfere with the stability of the preparation; on the other hand, moisture absorption will affect the appearance of the preparation, Migration of active ingredients is caused, although it can be improved by strengthening the packaging, but it is still difficult to ensure the quality of the preparation in the case of abnormal environment, and it will also increase the cost of drug production. And it is not conducive to the use of hypertensive patients with diabetes; another commonly used disintegrating agent-polyvinylpyrrolidone is not suitable for use in the present invention, which will cause the dissolution rate of long-term placed test samples to decline.

We have carried out in-depth research on the physical and chemical properties of valsartan and hydrochlorothiazide, especially through the screening of auxiliary materials, prescriptions and long-term investigations, to effectively solve the above problems. Further research on this basis has completed the present invention. Compared with the existing oral solid preparations, the preparation of the present invention has stable quality and quickly reaches the peak blood concentration after oral administration, and the relative bioavailability is significantly improved, and this effect cannot be predicted by those skilled in the art.

Both valsartan and hydrochlorothiazide are insoluble in water, and their dissolution rate is generally low when using general-purpose excipients, or their dissolution rate decreases with the prolongation of storage time. On the one hand, it should be emphasized to improve its hydrophobicity, and on the other hand, it is necessary to add hydrophilic excipients that are conducive to improving the dissolution of valsartan and hydrochlorothiazide. The auxiliary material is selected from: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and various anhydrous calcium salts. Preferred: mannitol, microcrystalline cellulose, calcium sulfate, anhydrous calcium hydrogen phosphate.

The excipients used in ordinary tablets and capsules cause the disintegration time of the preparation to be too long. On the one hand, a compound disintegrant is selected, and on the other hand, the method of internal and external addition is adopted to improve it. Described disintegrating agent comprises disintegrating agent and disintegrating accelerator, and wherein disintegrating agent is selected from: sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose; Accelerating disintegrating agent is selected from: sodium lauryl sulfate, One of sodium dodecyl sulfonate, Tween-80 or their mixture. Tween-80, sodium lauryl sulfate are preferred.

For valsartan and hydrochlorothiazide are comparatively viscous, the present inventor has strengthened the screening work of wetting agent. The test results show that the choice of wetting agent should be improved in the presence of a large amount of ethanol to prevent valsartan and hydrochlorothiazide from being too viscous in water to be granulated, or to prolong the disintegration time; The use of vegetarian substances can not only avoid the softness of the particles caused by the large amount of ethanol so that it is difficult to compress the tablet, but also improve the uniformity of the preparation in the dispersed state.

Through a large number of screening tests, we surprisingly found that the combination of micronized silica gel and talcum powder has an ideal effect as a lubricant. It not only guarantees rapid disintegration, but also greatly helps to improve the dissolution rate.

The present invention will be further described without limitation below.

active ingredient

Based on the weight of valsartan and hydrochlorothiazide, each tablet contains 10-500 mg of valsartan, preferably 40-320 mg, more preferably 80-160 mg; each tablet contains 5-50 mg of hydrochlorothiazide, preferably 10-25 mg. In order to improve the dissolution rate of the preparation more effectively, it is more advantageous to pretreat the active ingredient by pulverizing it to a size above 100 mesh, preferably above 120 mesh, or even micronized.

filler

If the active ingredient (the weight sum of valsartan and hydrochlorothiazide) is calculated as 1 part, then

The filler is 0.05-10 parts, preferably: 0.1-5 parts, more preferably 0.2-3 parts. Selected from: Mannitol, microcrystalline cellulose, hydroxypropyl cellulose, various anhydrous calcium salts. Preferred: mannitol, microcrystalline cellulose, calcium sulfate, anhydrous calcium hydrogen phosphate.

Disintegrants : including disintegrants and disintegrators

The disintegrant is 0.01-1 part, preferably: 0.03-0.5 part, more preferably 0.05-0.3 part. Selected from: sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose.

The disintegration accelerator is 0.001-0.5 parts, preferably: 0.01-0.3 parts, more preferably 0.02-0.2 parts. Selected from: sodium lauryl sulfate, sodium lauryl sulfate, Tween 80 or their mixture. Tween-80, sodium lauryl sulfate are preferred.

The amount of lubricant is 0.001-0.5 part, 0.01-0.3 part, more preferably 0.02-0.2 part. Selected from: micronized silica gel and talc.

We have surprisingly found that adding the above-mentioned auxiliary materials when preparing the dispersible tablet of the present invention not only makes the dispersible tablet stable, but also disintegrates rapidly and has a quick onset of action. The test results show that the dispersible tablet has no adverse phenomena such as slow disintegration and decreased dissolution after long-term storage, which is extremely beneficial for maintaining the bioavailability of the drug. Therefore, it can be considered that, in addition to the characteristics of the dispersible tablet preparation, the preparation of the present invention also has the advantages of stable active ingredients, reaching peak value rapidly and significantly improved bioavailability.

Other accessories

Advantageously, in order to make the dispersible tablet more stable and feel better in all aspects, the present invention can optionally further add flavoring agents, such as aspartame, stevioside, proteosaccharides and the like.

Thus, the present invention provides a dispersible tablet containing valsartan and hydrochlorothiazide, comprising:

a. Based on the weight of valsartan and hydrochlorothiazide, each tablet contains 50-500 mg of valsartan, preferably 80-160 mg; each tablet contains 5-50 mg of hydrochlorothiazide, preferably 10-25 mg.

b. If the active ingredient (the weight sum of valsartan and hydrochlorothiazide) is calculated as 1 part, the content of the auxiliary material is 0.05-15 parts. Preferably 0.2-7 parts, more preferably 0.3-4 parts.

The above-mentioned auxiliary materials include fillers, disintegrating agents, disintegrating accelerators, lubricants, and wetting agents.

The present invention does not impose specific limitations on the preparation method of the dispersible tablet, and conventional methods in the art, such as wet granulation, can be used. There is no specific limitation on the appearance shape of the dispersible tablet, and it can be any existing shape.

The following examples are intended to further illustrate the present invention, but not to limit the scope of the present invention. Modifications and changes to the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

specific implementation plan

Embodiment 1: prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 320mg

Hydrochlorothiazide 12.5mg

Microcrystalline Cellulose 150mg

Mannitol 100mg

Sodium carboxymethyl starch 40mg

Low-substituted hydroxypropyl cellulose 10mg

Micropowder silica gel 10mg

Talc powder 5mg

Stevia 5mg

3% hypromellose in 90% ethanol solution Appropriate amount

Total tablet weight 652.5mg

Process:

Get the raw materials of valsartan and hydrochlorothiazide, pulverize them, pass through a 200-mesh sieve, and set aside.

According to the prescription quantity, take valsartan and hydrochlorothiazide, microcrystalline cellulose, mannitol, stevioside and carboxymethyl starch sodium and mix evenly through a 100-mesh sieve, pour into the soft material made of adhesive, pass through a 40-mesh sieve to granulate, Dry at 55°C, granulate with 40 mesh, add low-substituted hydroxypropyl cellulose, micro-powder silica gel, and talcum powder that have passed through a 100-mesh sieve, mix evenly, test, adjust tablet weight, compress, test, and pack.

Embodiment 2: prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 80mg

Hydrochlorothiazide 25mg

Calcium Sulfate 50mg

Microcrystalline Cellulose 100mg

Low-substituted hydroxypropyl cellulose 30mg

Micropowder silica gel 5mg

Talc powder 5mg

Aspartame 5mg

75% ethanol solution of 2% hypromellose in appropriate amount

Total tablet weight 300mg

Process:

According to the prescription amount, weigh valsartan, hydrochlorothiazide, calcium sulfate, microcrystalline cellulose, aspartame and 3/4 of the prescription amount of low-substituted hydroxypropyl cellulose, pass through a 100-mesh sieve and mix evenly, pour into the adhesive Prepare soft material, granulate through 20 mesh sieve, dry at 50°C, granulate with 20 mesh, add micropowder silica gel, talcum powder and remaining low-substituted hydroxypropyl cellulose that have passed through 100 mesh sieve, mix evenly, test, and adjust tablet weight , compressed into tablets, inspected, packaged, and obtained.

Embodiment 3: Prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 320mg

Hydrochlorothiazide 25mg

Mannitol 75mg

Calcium Sulfate 75mg

Carboxymethyl Starch Sodium 50mg

Low-substituted hydroxypropyl cellulose 10mg

Sodium Lauryl Sulfate 15mg

Micropowder silica gel 10mg

Talc powder 10mg

Protein sugar 20mg

95% ethanol solution of 5% hypromellose in appropriate amount

Total tablet weight 610mg

Process:

Get the raw materials of valsartan and hydrochlorothiazide, pulverize them, pass through a 180-mesh sieve, and set aside.

According to the prescription amount, weigh valsartan, hydrochlorothiazide, mannitol, calcium sulfate, sodium starch glycolate, sodium lauryl sulfate, protein sugar, pass through a 100 mesh sieve and mix evenly, pour into soft material made of adhesive, pass Granulate with a 18-mesh sieve, dry at 60°C, granulate with a 20-mesh sieve, add micropowder silica gel, talcum powder and low-substituted hydroxypropyl cellulose that have passed through a 100-mesh sieve, mix evenly, test, adjust tablet weight, compress, test, and pack , that is.

Embodiment 4: prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 80mg

Hydrochlorothiazide 12.5mg

Calcium hydrogen phosphate anhydrous 150mg

Microcrystalline Cellulose 200mg

Carboxymethyl Starch Sodium 50mg

Micropowder silica gel 5mg

Talc powder 5mg

Stevia 3mg

1% hypromellose in 70% ethanol solution qs

Total tablet weight 505.5mg

Process:

According to the prescription amount, weigh valsartan and hydrochlorothiazide, anhydrous calcium hydrogen phosphate, microcrystalline cellulose, 3/4 sodium carboxymethyl starch, micropowder silica gel, stevioside, pass through a 100 mesh sieve and mix evenly, pour into the adhesive preparation Soft material, pass through 24 mesh sieve, dry at 55°C, granulate with 24 mesh, add talcum powder and remaining sodium starch glycolate, mix evenly, test, adjust tablet weight, compress tablet, test, pack, and get ready.

Embodiment 5: prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 160mg

Hydrochlorothiazide 12.5mg

Calcium hydrogen phosphate anhydrous 50mg

Mannitol 100mg

Low-substituted hydroxypropyl cellulose 20mg

Tween-80 3mg

Micropowder silica gel 5mg

Talc powder 2mg

Aspartame 3mg

3% hypromellose in 75% ethanol solution qs

Total tablet weight 355.5mg

Process:

Get the raw materials of valsartan and hydrochlorothiazide, pulverize them, pass through a 120-mesh sieve, and set aside.

According to the prescription amount, weigh valsartan, hydrochlorothiazide, anhydrous calcium hydrogen phosphate, 3/4 low-substituted hydroxypropyl cellulose, mannitol, micropowder silica gel, aspartame, pass through 100 sieves and mix evenly, pour into viscous Mixture and soft material made of Tween-80, pass through 40 mesh sieve, dry at 55°C, granulate with 40 mesh, add talc powder and remaining low-substituted hydroxypropyl cellulose, mix evenly, test, adjust tablet weight, and compress , inspection, packaging, that is.

Embodiment 6: prescription (calculated in single tablet)

Component Content (mg/tablet)

Valsartan 160mg

Hydrochlorothiazide 25mg

Microcrystalline Cellulose 120mg

Mannitol 100mg

Carboxymethyl Starch Sodium 40mg

Sodium Lauryl Sulfate 5mg

Micropowder silica gel 5mg

Talc powder 2mg

Stevia 5mg

2% hypromellose in 90% ethanol solution qs

Total tablet weight 462mg

Process:

Get valsartan and hydrochlorothiazide raw materials, pulverize, pass through a 140 mesh sieve, and set aside.

According to the prescription amount, weigh valsartan, hydrochlorothiazide, microcrystalline cellulose, mannitol, 3/4 sodium carboxymethyl starch, sodium lauryl sulfate, stevia, pass through a 100-mesh sieve and mix evenly, pour into the adhesive Make soft material, pass through 40 mesh sieve, dry at 55°C, granulate with 40 mesh, add micropowder silica gel, talcum powder and the remaining sodium starch glycolate, mix evenly, test, adjust tablet weight, compress, test, pack, and get ready .

Comparative Test 1: In Vitro Dissolution Test

Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel is used as filler; water-acetonitrile (1:1) is adjusted to pH=2.5 with phosphoric acid as mobile phase; detection wavelength is 272nm; flow rate is 0.8mL/min ; The number of theoretical plates should not be less than 1500 based on the calculation of the valsartan peak

Dissolution assay method: get each test sample, according to dissolution assay (Chinese Pharmacopoeia 2000 edition two appendix XC first method), with pH6.8 phosphate buffer (get 6.8g potassium dihydrogen phosphate and 0.9g hydroxide Sodium, add water 1000mL, shake up) 900mL is solvent, and rotating speed is 100 revolutions per minute, operate according to law, after 15 minutes, get solution 5mL, filter, get continued filtrate and make need testing solution; valsartan and hydrochlorothiazide reference substances in appropriate amounts to prepare a solution containing about 80 μg/mL of valsartan and 12.5 μg/mL of hydrochlorothiazide reference substances. According to the above-mentioned chromatographic conditions, inject samples and record the chromatogram; calculate the dissolution amount of each tablet with the peak area according to the external standard method.

The test results are as follows

For the test samples of dispersible tablets with different prescriptions, the dissolution amount has reached more than 80% of the labeled amount in 5 minutes, and the dissolution amount has approached more than 100% of the labeled amount in 15 minutes; while the dissolution of ordinary tablets of valsartan and hydrochlorothiazide has just reached 50% in 5 minutes. 50%, and the dissolution is nearly complete in 30 minutes, and the difference between the two is significant.

Comparative Test 2 Bioavailability

The plasma concentrations of valsartan and hydrochlorothiazide were determined by reversed-phase high-performance liquid chromatography, and the relevant pharmacokinetic parameters were calculated by the 3P87 pharmacokinetic program. Tan and hydrochlorothiazide (80 mg of valsartan and 12.5 mg of hydrochlorothiazide), respectively select the sample of Example 4 and the ordinary tablets of valsartan and hydrochlorothiazide sold on the market to test, and evaluate the relative bioavailability of the two. The results show that the preparation of the invention significantly improves the absorption and utilization in the body, significantly increases the bioavailability, and is significantly better than the existing common tablets.

Table 1: Comparative test results

Claims (2)

1. a kind of dispersible tablet of valsartan and hydrochlorothiazide, is made up of valsartan, hydrochlorothiazide and pharmaceutical auxiliary material of therapeutically effective dose: a. Based on valsartan and hydrochlorothiazide, each tablet contains 10-500 mg of valsartan and 5-50 mg of hydrochlorothiazide; b. Pharmaceutical excipients include fillers, disintegrants, disintegrators, lubricants, The filler is selected from: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, various anhydrous calcium salts; The disintegrating agent is selected from: sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose; The disintegrating agent is selected from: sodium lauryl sulfate, sodium lauryl sulfate, Tween 80 or their mixture; The lubricant is selected from: micronized silica gel and talcum powder; Wherein the sum of valsartan and hydrochlorothiazide weight is calculated as 1 part, The filler is 0.05 to 10 parts; The disintegrant is 0.01 to 1 part; The disintegration accelerator is 0.001 to 0.5 parts; The lubricant is 0.001 to 0.5 parts. 2. the dispersible tablet of valsartan and hydrochlorothiazide according to claim 1, is characterized in that: Each tablet contains 80-160 mg of valsartan and 12.5-25 mg of hydrochlorothiazide.