CN113855648B

CN113855648B - Acetazolamide sustained-release capsule and preparation method thereof

Info

Publication number: CN113855648B
Application number: CN202111466355.6A
Authority: CN
Inventors: 陈艳; 蔡咏坡; 费宇杰
Original assignee: Beijing Lianjia Pharmaceutical Technology Development Co ltd
Current assignee: Beijing Lianjia Pharmaceutical Technology Development Co ltd
Priority date: 2021-12-03
Filing date: 2021-12-03
Publication date: 2022-02-25
Anticipated expiration: 2041-12-03
Also published as: CN113855648A

Abstract

The invention provides an acetazolamide sustained-release capsule and a preparation method thereof, wherein the content of the acetazolamide sustained-release capsule is acetazolamide sustained-release pellets, waxy materials are used in the sustained-release pellets, wet pellets are obtained by wet granulation-extrusion spheronization, and the wet pellets are dried at a temperature close to the melting point of the waxy materials, so that pellet particles obtain sustained-release characteristics. The obtained acetazolamide sustained-release capsule is a sustained-release preparation which is taken once a day, and compared with a quick-release preparation, the acetazolamide sustained-release capsule reduces the times of daily taking and side effects, and improves the compliance of patients.

Description

Acetazolamide sustained-release capsule and preparation method thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to an acetazolamide sustained-release capsule and a preparation method thereof.

Background

Acetazolamide (Acetazolamide) is a carbonic anhydrase inhibitor, can inhibit the activity of ciliary body skin carbonic anhydrase, thereby reducing aqueous humor formation and lowering intraocular pressure, and is suitable for treating various types of glaucoma, such as open-angle (chronic simple) glaucoma and angle-closure glaucoma. The foreign clinical research shows that the acetazolamide can be used for preventing symptoms such as headache, nausea, shortness of breath, dizziness, lethargy, fatigue and the like caused by acute altitude reaction, the lung function (such as ventilation volume per minute, vital capacity and expiratory peak flow) of a subject taking the acetazolamide is superior to that of a control group, and a climber taking the acetazolamide has less sleep disorder.

At present, only quick-release tablets of acetazolamide are available on the market in China, and the acetazolamide needs to be taken 2-3 times a day. Glaucoma occurs mainly in the elderly, often accompanied by memory decline with age, and therefore providing a once-daily acetazolamide sustained release formulation will improve compliance of the elderly with medication; meanwhile, the sustained-release preparation can provide relatively stable blood concentration, and avoids side effects caused by overhigh peak value due to multiple times of single-day administration.

The slow release formulation of acetazolamide marketed in the United states of AmericaDIAMOX of^®SEQUELS^®. In addition, CN102949377A of Shuaishui medicine science and technology development Limited company in south of river discloses a sustained-release capsule of acetazolamide, which is DIAMOX^®SEQUELS^®The imitation drug of (1).

The acetazolamide is white needle crystal or crystalline powder, and has no odor and slightly bitter taste. Slightly soluble in boiling water, slightly soluble in water or ethanol, and hardly soluble in chloroform or diethyl ether; it is easy to dissolve in ammonia solution. Due to the solubility characteristics of acetazolamide, in DIAMOX^®SEQUELS^®And CN102949377A both used a combination of microcrystalline cellulose and sodium lauryl sulfate for the preparation of sustained release capsules by wet granulation. The surfactant sodium dodecyl sulfate in the formula can promote the dissolution of acetazolamide, but the content of the sodium dodecyl sulfate is only 0.1-0.5%, so that the problem of uneven mixing is easily caused in the preparation process, and the release uniformity of a unit sustained-release capsule is further influenced.

Sodium dodecyl sulfate is used for controlling DIAMOX^®SEQUELS^®And key components of sustained-release property of imitation drug, development of sustained-release preparation without surfactant such as sodium dodecyl sulfate, etc., and realization of DIAMOX^®SEQUELS^®Similar release effects will face great technical challenges in formulation development.

Disclosure of Invention

The inventor unexpectedly found that acetazolamide wet pills prepared by wet granulation-extrusion spheronization by using a waxy material can be prepared into release characteristics with the release degree maintained for 12 hours in an in vitro dissolution experiment after being dried for a certain time within the temperature range of the melting point of the waxy material. Compared with the 12-hour drug effect of the quick-release preparation, the drug effect of the sustained-release capsule can be prolonged to 24 hours in vivo after administration, so that the administration frequency is reduced, and the side effect of administration is reduced.

The invention aims to provide an acetazolamide sustained-release capsule, wherein the capsule content comprises acetazolamide sustained-release pellets, and the sustained-release pellets comprise 500 parts by weight of acetazolamide and 30-100 parts by weight of a pharmaceutically acceptable waxy material.

In some embodiments, the pharmaceutically acceptable waxy material is used in an amount of 30 to 70 or 35 to 65 parts by weight.

In some embodiments, the pharmaceutically acceptable waxy material is selected from one or more of carnauba wax, glyceryl behenate, cetyl esters wax, stearic acid, preferably glyceryl behenate or carnauba wax.

In some embodiments, the acetazolamide sustained release pellets further comprise a filler, and a binder.

In some embodiments, the filler is selected from one or more of microcrystalline cellulose, starch, lactose, sucrose, mannitol, sorbitol, isomalt, microcrystalline cellulose, and may be PH101, PH102, or the like.

In some embodiments, the binder is selected from povidone, hydroxypropylmethylcellulose, copovidone. Preferably povidone. The polyvidone includes one or more of polyvidone K17, polyvidone K25, polyvidone K30, polyvidone K60 or polyvidone K90, preferably polyvidone K30.

In some embodiments, the amount of filler in the sustained release pellets is 16 to 60 parts by weight. Preferably 25-55, 30-55, 40-55 parts by weight. Specific amounts of fillers may be 26.5, 40, 41.8 parts by weight.

In some embodiments, the binder is present in the sustained release pellets in an amount of 15 to 25 parts by weight. Preferably 15-20, 18-19.5 parts by weight. The binder may be used in particular in amounts of 19.5, 18.0, 18.9 parts by weight.

In some embodiments, a lubricant is added to the exterior of the sustained release pellet. The lubricant is one or more selected from magnesium stearate, calcium stearate, zinc stearate, sucrose stearate, stearic acid, silicon dioxide, pulvis Talci, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and sodium stearyl fumarate. Talc is preferred.

In some embodiments, the lubricant is specifically used in an amount of 6 to 7 parts by weight.

In some embodiments, the amount of acetazolamide in the contents of the extended release capsule is 75-85 w/w%. The specific weight percentage of acetazolamide may be 76.9%, 83.3%, or 79.4%.

In some embodiments, the amount of pharmaceutically acceptable waxy material in the contents of the extended release capsule is 4-12w/w%, preferably 5-10%. Specific weight percentages of pharmaceutically acceptable waxy materials may be 6.0%, 8.0%, 10%.

In some embodiments, the amount of filler in the contents of the extended release capsule is 2-10w/w%, preferably 1-8%, 2.5-7%. The specific weight percentage of the filler may be 2.7%, 4.1%, 6.7%, 6.6%.

In some embodiments, the amount of binder in the contents of the extended release capsule is 2-5 w/w%. The specific weight percentage of the binder may be 2%, 3%, 4%, 5%.

In some embodiments, the amount of lubricant in the contents of the extended release capsule is 1-2 w/w%.

The invention aims to provide a preparation method of an acetazolamide sustained-release capsule composition, which is characterized in that the components of the sustained-release pellets in the prescription amount are prepared into wet pellets, and the wet pellets are dried within the temperature range of the melting point of a waxy material.

In some embodiments, the method of preparing the acetazolamide sustained release capsule composition comprises the steps of:

step 1: uniformly mixing acetazolamide, a filling agent, a waxy material and an adhesive in a prescription amount;

step 2: adding a wetting agent, and stirring and cutting to prepare a soft material;

and step 3: making the soft material into wet pellet by extruding and rounding machine;

and 4, step 4: drying the wet pellets in the temperature range of the melting point of the waxy material;

and 5: adding the lubricant into the dried pellets and uniformly mixing;

step 6: filling the lubricated mixture into a capsule shell to prepare a capsule preparation.

In some embodiments, the temperature at which the waxy material melts in step 4 ranges from 65 ℃ to 86 ℃. In preferred embodiments, the temperature at which the waxy material melts in step 4 is in the range of 65-77 ℃ or 80-86 ℃.

In some embodiments, the extrusion spheronizer extrusion screen in step 3 has a mesh diameter of 1.0 mm.

In some embodiments, the drying time in step 4 is 1.5 to 4 hours. Specifically, the time may be 1.5, 2, 2.5, 3, 3.5 or 4 hours.

In some embodiments, the diameter of the extrusion mesh in step 3 is 1.0mm, the spheronization speed is 1000-.

In some embodiments, an acetazolamide extended release capsule composition is provided, wherein prescribed amounts of the ingredients in the extended release pellets are prepared as wet pellets, and the wet pellets are dried at a temperature within the melting point range of the waxy material.

Advantageous effects

1. The sustained-release capsule provided by the invention does not use sodium dodecyl sulfate, so that the problem that the release uniformity of a unit-dose sustained-release capsule is influenced due to uneven mixing of the sodium dodecyl sulfate in wet granulation is solved.

2. The sustained-release capsule provided by the invention realizes the stable release of the slightly soluble drug acetazolamide under the condition that a surfactant, namely sodium dodecyl sulfate, is not used.

3. The invention unexpectedly discovers that acetazolamide wet pills prepared by wet granulation-extrusion spheronization by using a waxy material are dried for a certain time at a temperature within the melting point range of the waxy material, so that the distribution form of the waxy material in the pellets is changed, a slow release effect is generated, and the slow release can be maintained for 12 hours in an in vitro dissolution experiment.

Drawings

FIG. 1 is a release profile of a sustained-release capsule of acetazolamide of comparative example 1.

FIG. 2 is a release profile of the acetazolamide extended release capsule of example 1-2.

FIG. 3 is a release profile of the acetazolamide extended release capsule of example 3.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiment is a module embodiment of the present invention, not a whole embodiment. Elements and features described in one embodiment of the invention may be combined with elements and features shown in one or more other embodiments. It should be noted that the illustration omits illustration and description of components and processes not relevant to the present invention that are known to those of ordinary skill in the art for clarity purposes. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.

Method for measuring release:

taking the product of the example, according to a release rate determination method (first method of appendix X D of the second part of the 2010 edition of Chinese pharmacopoeia), adopting a dissolution rate second method device, wherein a release medium is pH 4.5 acetate buffer solution, contains 2.2% of Tween 20, has a medium volume of 900ml, adopts a paddle method and a rotating speed of 75rpm, uses a settling basket, has a release medium temperature of 37 +/-0.5 ℃, takes 10ml of solution respectively in 1, 2, 5 and 12 hours, filters the solution by using a 0.45 mu m filter membrane, and instantly supplements 10ml of the buffer solution; taking the subsequent filtrate as a test solution; and taking about 20mg of acetazolamide as a reference substance, putting the acetazolamide into a 50ml measuring flask, adding 2ml of methanol for dissolving, and diluting the acetazolamide to a scale by using a release medium to obtain a reference substance solution. According to high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia), octyl silane bonded silica gel is used as a filler (Agilent Eclipse XDB-C8, 4.6 x 150mm, 5 mu m or a chromatographic column with equivalent efficiency); methanol-water (30: 70) is used as a mobile phase; the detection wavelength is ultraviolet 292 nm; the column temperature is 30 ℃; the flow rate was 1.0ml per minute; the running time was 10 minutes; the injection volumes of the reference substance and the sample solution are respectively 10 mul, and the release amount at different times is respectively calculated by peak areas according to an external standard method.

Comparative example 1

Comparative example 1 the formulation composition of acetazolamide sustained release capsules (specification 500 mg/capsule) is shown in table 1.

TABLE 1 composition of comparative example 1 formulation

The preparation method comprises the following steps:

step 1: weighing acetazolamide, microcrystalline cellulose, carnauba wax and povidone according to the prescription amount, adding into a wet granulator, stirring, and mixing at the speed of 20rpm for 5 minutes to prepare a uniformly mixed premix;

step 2: adding a proper amount of water as a granulating solvent in the step 1, stirring and cutting at the stirring speed of 300-;

and step 3: passing the soft material through an extrusion spheronizer, wherein the diameter of an extrusion sieve pore is 1.0mm, the spheronization speed is 1000-1500rpm, and the spheronization time is 40-80 seconds, so as to prepare wet pellets;

and 4, step 4: drying the wet pellets at 40 ℃ for 2 hours;

and 5: adding talcum powder into the dried pellets, mixing at the speed of 20rpm for 5 minutes, and uniformly mixing;

step 6: filling the lubricated pellets into a No. 00 capsule shell to prepare a capsule preparation.

And (3) measuring the release degree:

the release profile of comparative example 1 is shown in figure 1. As can be seen from fig. 1, although the carnauba wax of comparative example 1 has a component ratio as high as 15%, the release rate does not exhibit a sustained release characteristic without heat-drying at a temperature near its melting point.

Comparative example 2

Comparative example 2 the formulation composition of acetazolamide sustained release capsules (specification 500 mg/capsule) is shown in table 2. Comparative example 2 did not use povidone, as compared to comparative example 1.

TABLE 2 comparative example 2 formulation composition

The preparation method is the same as that of comparative example 1.

Comparative example 2 the formulation produced dry pellets that yielded more fines (about 30%), pellets that were less formable and physically less strong, and the formulation was not suitable for the preparation of sustained release pellets.

Comparative example 3

Comparative example 3 the formulation composition of acetazolamide sustained release capsules (specification 500 mg/capsule) is shown in table 3. In comparison with comparative example 1, comparative example 3 did not use microcrystalline cellulose.

TABLE 3 composition of comparative example 3 formulation

The preparation method is the same as that of comparative example 1.

Comparative example 3 the wet pellets prepared with the formulation showed a hardened appearance during the drying process, the pellets had uneven size, poor roundness, and no reproducible release, and the formulation was not suitable for the preparation of sustained release pellets.

Comparative example 4

Comparative example 4 the formulation composition of acetazolamide sustained release capsules (specification 500 mg/capsule) is shown in table 4. The amount of povidone used in comparative example 4 was increased to 7% compared to comparative example 1.

TABLE 4 comparative example 4 formulation composition

The preparation method is the same as that of comparative example 1.

The formulation of comparative example 4 showed that the extrudate could not be cut into pellets of suitable roundness during the extrusion spheronization step, but rather appeared as long strips after spheronization, which was detrimental to subsequent capsule filling, indicating that povidone that was too high in the formulation was detrimental to the preparation of pellets with good roundness.

Examples 1 to 2

The formulation of the acetazolamide sustained release capsules of examples 1-2 (specification 500 mg/capsule) is shown in Table 5.

TABLE 5 examples 1-2 recipe compositions

The preparation method comprises the following steps:

steps 1-3 and steps 5-6 of examples 1-2 were the same as in comparative example 1;

and 4, step 4: the melting point of carnauba wax is 80-86 deg.C, and the wet pellets are dried at 85 deg.C for 2 hr.

And (3) measuring the release degree:

the release profile for examples 1-2 is shown in FIG. 2. As can be seen from fig. 2, the wet pellets of examples 1-2 provided a slow release of 12 hours after being heated at a temperature close to the melting point of carnauba wax, even though the amount of carnauba wax formulation was lower than that of comparative example 1, indicating that the high temperature drying process had a large effect on the release rate; and the greater the prescribed amount of carnauba wax, the slower the release.

Example 3

The prescription composition of the acetazolamide sustained-release capsule (specification is 500 mg/capsule) of example 3 is shown in Table 6.

Table 6 example 3 prescription composition

The preparation method comprises the following steps:

steps 1 to 3 and steps 5 to 6 of example 3 were the same as in comparative example 1;

and 4, step 4: the melting point of glyceryl behenate is 65-77 deg.C, and the wet pellets are dried at 70 deg.C for 2 hr.

And (3) measuring the release degree:

the release profile of example 3 is shown in figure 3. As can be seen from fig. 3, the wet pellets of example 3 provided a slow release of 12 hours after heating at a temperature near the melting point of glyceryl behenate.

Release similarity determination:

the release degree comparison was performed in 4 media of pH =1.0 hydrochloric acid solution, pH =4.5 acetate buffer, pH =6.8 phosphate buffer and water, using f₂Analogy factor method for example 1 sustained release capsules and reference formulation DIAMOX^® SEQUELS^®Dissolution rate evaluation was performed. Degree of release and f₂ResultsSee Table 7, in 4 media f₂Are all larger than 80, and have dissolution consistency with the original product in vitro.

Table 7 release rates and similarity factors f for example 1 and the reference formulation under different release media₂Results

Claims

1. An acetazolamide sustained-release capsule is characterized in that the capsule content comprises acetazolamide sustained-release pellets, and the sustained-release pellets comprise 500 parts by weight of acetazolamide, 30-100 parts by weight of pharmaceutically acceptable waxy materials, 16-60 parts by weight of fillers and 15-25 parts by weight of adhesives; the pharmaceutically acceptable waxy material is selected from one or more of carnauba wax, glyceryl behenate, cetyl alcohol ester wax and stearic acid; the filler is selected from one or more of microcrystalline cellulose, starch, lactose, sucrose, mannitol, sorbitol and isomalt; the adhesive is selected from one or more of povidone, copovidone and hydroxypropyl methylcellulose; the preparation method of the acetazolamide sustained-release capsule comprises the steps of preparing the components of the sustained-release pellets in the prescription amount into wet pellets by using a wetting agent, and drying the wet pellets in the temperature range of the melting point of a waxy material.

2. The acetazolamide sustained-release capsule of claim 1, wherein the temperature at which said waxy material melts is in the range of 65-86 ℃.

3. The acetazolamide sustained-release capsule of claim 2, wherein a lubricant is added outside the sustained-release pellets, and the amount of the lubricant is 6 to 7 parts by weight.

4. An acetazolamide sustained-release capsule is characterized by comprising the following components: 75-85w/w% of acetazolamide, 4-12w/w% of pharmaceutically acceptable waxy materials, 2-10w/w% of filling agents, 2-5w/w% of binding agents and 1-2w/w% of lubricating agents, wherein the total amount of the components is 100%; the pharmaceutically acceptable waxy material is selected from one or more of carnauba wax, glyceryl behenate, cetyl alcohol ester wax and stearic acid; the filler is selected from one or more of microcrystalline cellulose, starch, lactose, sucrose, mannitol, sorbitol and isomalt; the adhesive is selected from one or more of povidone, copovidone and hydroxypropyl methylcellulose; the preparation method of the acetazolamide sustained-release capsule comprises the steps of preparing the components of the sustained-release pellets in the prescription amount into wet pellets by using a wetting agent, and drying the wet pellets in the temperature range of the melting point of a waxy material.

5. The process for preparing acetazolamide sustained release capsules according to any one of claims 1 to 4, characterized in that it comprises the following steps:

and 4, step 4: drying the wet pellets in the temperature range of the melting point of the waxy material, wherein the temperature range of the melting point of the waxy material is 65-86 ℃;

and 5: adding the lubricant into the dried pellets and uniformly mixing;

6. The method of claim 5, wherein the melting point of the waxy material in step 4 is in the range of 65 ℃ to 77 ℃ or 80 ℃ to 86 ℃.

7. The method according to claim 6, wherein the screen hole diameter of the extrusion screen of the extrusion spheronizer in the step 3 is 1.0 mm.

8. The method according to claim 7, wherein the drying time in step 4 is 1.5 to 4 hours.

9. The process according to claim 8, wherein the diameter of the extrusion mesh in step 3 is 1.0mm, the spheronization speed is 1000-.

10. An acetazolamide extended release capsule prepared using the method of any one of claims 5-9.