CN103860515A - Azithromycin osmotic pump controlled release tablet and preparation method thereof - Google Patents

Abstract

The invention relates to an azithromycin osmotic pump controlled release tablet and a preparation method thereof. The azithromycin osmotic pump controlled release tablet is formed by a tablet core and a semipermeable film coating with small holes, wherein the tablet core includes 20-80wt% of azithromycin, 5-50wt% of an acidic cosolvent, 5-50wt% of a skeleton matrix and 1-60wt% of a pharmaceutically acceptable auxiliary material, and the acidic cosolvent is an organic acid, an inorganic acid or a composition thereof. The preparation method of the azithromycin osmotic pump controlled release tablet comprises the steps of granulating, tabletting, coating with the semi-permeable film coating, and punching.

Description

Azithromycin osmotic pump controlled-release tablet and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to azithromycin single-layer and double-layer osmotic pump controlled-release tablets and a preparation method thereof.

Background technique

The structural formula of azithromycin is as follows, and its chemical name is: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-dideoxy-3-C-methyl- 3-O-methyl-α-L-nucleo-hexapyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14- Heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xyl-hexapyranosyl]oxy]-1-oxa-6-azacycle Pentadecan-15-one.

Azithromycin belongs to the 15-membered ring macrolide antibiotics, has a broader antibacterial spectrum than erythromycin, and has a strong inhibitory effect on Haemophilus influenzae and β-lactamase-producing bacteria. Azithromycin has a unique phagocytic delivery mechanism in the body, that is, after administration, azithromycin is quickly concentrated in polymorphonuclear leukocytes (PMN) and macrophages, and is transported to the infection site along with the migration of phagocytes, making the infected tissue Has a high concentration and keeps for a long time. At the same time, this transport mechanism determines its unique pharmacokinetic properties. Compared with β-lactams, macrolides and quinolones, it has a higher volume of distribution and a longer elimination half-life (tissue half-life). The period is 68~76h, the plasma half-life is 35~48h), wider cell permeability, and its tissue concentration can be 300 times higher than the extracellular concentration. At present, the commonly used oral dosage forms in clinical practice are tablets, and the specifications are 100mg/tablet, 125mg/tablet, 250mg/tablet or 500mg/tablet. There are two methods of administration: (1) 0.5 g daily on the first day, and 0.25 g daily on the 2nd to 5th day; (2) 0.5 g daily for 3 consecutive days. Azithromycin is a concentration-dependent antibiotic, and the two methods of administration can maintain the effective antibacterial concentration for 8 to 10 days.

Azithromycin has poor water solubility and low bioavailability in human body. Clinically, azithromycin and acid are often first made into corresponding azithromycin salts to increase its water solubility, and then made into corresponding preparations. However, azithromycin salts have poor stability in solution state. It is sensitive to acid, heat, oxidation and other factors, which brings unstable factors to its quality control. Azithromycin-N-oxide and 3'-descladinose Azithromycin are the oxidation and acid degradation products of azithromycin, and the acid degradation products are the main degradation forms (Zhang Dousheng, Wang Yuewen, Li Jin, etc., the impurity profile of domestic azithromycin for injection and its relationship with its composition Investigation on the Correlation of Salt Process [J]. Journal of Pharmaceutical Analysis, 2011, 31(8)). Moreover, complex processes such as freeze-drying, spray-drying, and reduced-pressure drying need to be used in the preparation process of the water-soluble salt of azithromycin.

As of January 2011, a total of nearly 40 enterprises across the country have obtained licenses for the production of azithromycin preparations. In addition, there are nearly 30 manufacturers applying for production approval documents, but most of the above-mentioned application and production drugs are generic injections , mainly for injection powder injections, ordinary tablets, capsules, dry suspensions, etc. In terms of sustained and controlled release oral preparations, only Pfizer (CN 1149831A) and Dow Pharmaceutical Company (CN 101861138A), but these two patents The in vitro tests of osmotic pump preparations are all carried out in buffer solution with pH 6.0 or in solution with pH 1.0 or the combination of the two solutions, neither of which is close to physiological conditions (most drugs are released in the small intestine, and the pH of the normal human small intestine environment is 6.8) The release simulation test of Pfizer's in vitro release test is only 6h.

According to the action mechanism and pharmacokinetic characteristics of azithromycin, in order to enhance the quality control of azithromycin and improve the tolerance of patients, the inventors of the present application prepared azithromycin osmotic pump tablets containing acidic co-solvent, and the process is simple.

Contents of the invention

One object of the present invention is to provide a kind of Azithromycin osmotic pump controlled-release tablet, described Azithromycin osmotic pump controlled-release tablet is made of tablet core and semipermeable film coating with aperture, wherein, based on the total weight of tablet core, The tablet core comprises 20-80wt%, preferably 30-60wt%, most preferably 35-50wt% azithromycin; 5-50wt%, preferably 5-30wt%, most preferably 5-15wt% acid cosolvent; 5-50wt% %, preferably 10-50wt%, most preferably 20-50wt% of the skeleton matrix and 1-60wt%, preferably 1-50wt% of pharmaceutically acceptable excipients.

The acidic cosolvent plays the role of regulating the osmotic pressure in the medicine chamber at the same time, and it is an organic acid, an inorganic acid or a combination thereof. Specifically, the acidic cosolvent is selected from citric acid, tartaric acid, lactobionic acid, malic acid, One or more of acid, fumaric acid, aspartic acid, preferably one or both selected from citric acid and tartaric acid, most preferably citric acid;

The skeleton matrix is selected from ethyl cellulose, hypromellose, hypromellose, sodium carboxymethyl cellulose, povidone, copovidone, carbomer, acrylic resin, stearic acid and One or more of octaols, preferably selected from povidone with a molecular weight of 2,500-3,000,000 and copovidone S-630 with a molecular weight of 30,000-60,000, most preferably with a molecular weight of 30,000 - 60000 copovidone S-630;

The pharmaceutically acceptable adjuvant includes one or more of binders, lubricants, opacifiers, fillers, colorants and osmotic pressure regulators, wherein the binder is selected from starch slurry, One or more of povidone, hypromellose, hypromellose, methyl cellulose, gelatin and polyethylene glycol, the preferred molecular weight is 2500-3000000 povidone; the lubricant is One or more selected from magnesium stearate, talcum powder, micropowder silica gel and polyethylene glycol, preferably one or both selected from magnesium stearate and talcum powder; the opacifier is One or more selected from titanium dioxide, talcum powder and silicon dioxide, preferably titanium dioxide; the filler is selected from one or more of microcrystalline cellulose, starch, dextrin, mannitol and calcium carbonate , preferably microcrystalline cellulose; the coloring agent is red iron oxide or yellow iron oxide; the osmotic pressure regulator is one or more selected from sodium chloride, potassium chloride, lactose, mannitol , preferably sodium chloride.

The weight gain of the semipermeable film coating is 3%-10% of the mass of the tablet core, preferably 5%-8%.

The semipermeable film coating includes a semipermeable membrane coating material and a permeability regulator, wherein the function of the semipermeable membrane coating material is to allow water to enter the inside of the controlled-release tablet to dissolve the drug and/or the osmotic pressure enhancer , which is one or more selected from cellulose acetate, cellulose acetate phthalate, acrylic resin and hydroxypropyl cellulose phthalate, preferably cellulose acetate with a molecular weight of 30000-50000; the transparent The main function of the regulator is to regulate the permeability of the semipermeable membrane, which is one or more selected from PEG4000, povidone, copovidone and hydroxypropyl cellulose, preferably PEG4000 with a molecular weight of 2600-3800.

The semipermeable coating film further includes a pharmaceutically acceptable plasticizer selected from phthalates, preferably diethyl phthalate with a molecular weight of 222.24.

Particularly, based on the weight of the osmotic pump tablet, the azithromycin controlled-release tablet comprises: 20-80wt%, preferably 30-60wt%, most preferably 35-50wt% of azithromycin; 5-50wt%, preferably 10-50wt% , most preferably 20-50wt% of PVPS-630 (copovidone S-630); 5-50wt%, preferably 5-30wt%, most preferably 5-15wt% of citric acid; 1-30wt%, preferably 1- 20wt%, most preferably 1-10wt% cellulose acetate; 0.1-30wt%, preferably 0.1-20wt%, most preferably 0.1-10wt% PEG4000.

The azithromycin osmotic pump controlled-release tablet can be a single-layer or double-layer osmotic pump controlled-release tablet.

When the azithromycin osmotic pump controlled-release tablet is a double-layer controlled-release tablet, the tablet core is composed of a drug-containing layer and a booster layer, wherein the booster in the booster layer includes polyoxyethylene, hypromellose, polyethylene glycol, etc. One or more of povidone, copovidone and carbomer, preferably one or both of povidone and copovidone.

When the azithromycin osmotic pump controlled-release tablet is a double-layer controlled-release tablet, the acidic cosolvent may exist in the drug-containing layer and/or the booster layer. When it exists in the drug-containing layer and the booster layer respectively, its distribution ratio is not limited, but its weight ratio can be 1:4-4:1, 1:3-3:1, 1:2.5-2.5 :1, 1:2-2:1, 1:1 (drug-containing layer: booster layer), etc.

Another object of the present invention is to provide a method for preparing the azithromycin osmotic pump controlled-release tablet, the method comprising:

Granulation: First weigh the components contained in each part of the tablet core (except the lubricant) according to the prescription amount, mix them evenly, and finally add the lubricant and mix well;

Tablet;

Semi-permeable membrane coating;

Hole punching: use laser or mechanical punching to punch small holes with a diameter of 0.2mm-1.2mm on one or more sides of the coated tablet.

Unless otherwise specified, the methods or processes used in the present invention are conventional methods and processes in the art.

In a single-layer osmotic pump, azithromycin reacts with an acidic co-solvent and dissolves in water to generate osmotic pressure, so it can be used as an osmotic pressure enhancer. Azithromycin can overflow from the small hole quickly, so copovidone is added to the tablet core and other viscous polymer materials.

In the double-layer osmotic pump, after the acid co-solvent in the booster layer is dissolved in water, it penetrates into the drug-containing layer and reacts with azithromycin. After being dissolved in water, osmotic pressure is produced, so it can be used as an osmotic pressure enhancer. Azithromycin can overflow from the small holes quickly, so copovidone and other viscous polymer materials are added to the tablet core.

According to the different specifications of azithromycin controlled-release tablets, this tablet can be prepared into a regular circular tablet, and the punching position of the regular tablet is fixed, usually at the center of the convex surface of the tablet.

The preparation method of the azithromycin monolayer osmotic pump controlled-release tablet comprises the following steps:

1) Weigh azithromycin, acid co-solvent, skeleton matrix and pharmaceutically acceptable excipients except lubricant according to the prescription, mix well, then add appropriate amount of lubricant, mix well;

2) tableting;

3) Coating, cellulose acetate-PEG4000 (9:1-5:1), acetone as solvent, until the weight of the tablet core reaches the designed amount;

4) Hole punching, using laser or mechanical punching to punch small holes with a diameter of 0.2mm-1.2mm on one or more sides of the coated tablet.

The preparation method of the azithromycin double-layer osmotic pump controlled-release tablet comprises the following steps:

1) Weigh and mix the sieved azithromycin, acidic co-solvent, skeleton matrix and pharmaceutically acceptable excipients except the lubricant according to the prescription amount, then add an appropriate amount of lubricant and mix well to obtain the drug-containing layer powder, spare;

2) Mix the acid co-solvent, the skeleton matrix and the pharmaceutically acceptable excipients except the lubricant evenly, then add an appropriate amount of lubricant, and mix well to get the booster layer powder, which is ready for use;

3) The drug-containing layer powder and the booster layer powder are compressed twice to obtain a double-layer tablet core;

4) Cover with semi-permeable film coat, cellulose acetate-PEG4000 (9:1-5:1), acetone as solvent, until the weight of the tablet core reaches the designed amount;

5) Drilling, using laser or mechanical drilling to punch small holes with a diameter of 0.2mm-1.2mm on one or more sides of the drug-containing layer of the coated tablet.

The present invention utilizes an acidic cosolvent, and azithromycin exists in the form of raw materials in single-layer and double-layer osmotic pumps, and the azithromycin and the acidic cosolvent only contact in physical form before contacting the solution, which avoids azithromycin produced in the preparation of salt The problem of drug instability is convenient for drug storage, that is, the azithromycin single-layer and double-layer osmotic pump controlled-release tablets of the present invention solve the problems of poor water solubility of azithromycin and poor stability in the preparation process of medicinal azithromycin salt, and the drug can be used at neutral The controlled-release release reaches 12 hours in medium water (the pH of water is 7, which is closer to the small intestine environment with pH 6.8), that is, the present invention is a pH-independent azithromycin osmotic pump controlled-release preparation. The preparation method of the azithromycin osmotic pump controlled-release tablet provided by the invention effectively solves the disadvantages of poor fluidity and compressibility after the compatibility of azithromycin and acid, and the process is simple, without using complex processes such as freeze drying, spray drying, and reduced pressure drying.

"Azithromycin" referred to in the present invention includes all amorphous and crystalline forms of azithromycin, including all co-crystals, co-precipitates, polymorphs, isomorphs, clathrates, solvates and hydrates , and anhydrous azithromycin, or a combination of the above forms.

Description of drawings

Fig. 1 is the release curve and common sheet release curve of the osmotic pump controlled-release tablet prepared by the prescription of Example 1;

Fig. 2 is the release curve and the common sheet release curve of the osmotic pump controlled-release tablet prepared by the prescription of Example 2;

Fig. 3 is the release curve and the common tablet release curve of the osmotic pump controlled-release tablet prepared by the prescription of Example 3;

Fig. 4 is the release curve and the common sheet release curve of the osmotic pump controlled-release tablet prepared by the prescription of Example 4;

Fig. 5 is the release curve and the common sheet release curve of the osmotic pump controlled-release tablet prepared by the prescription of Example 5;

Detailed ways

The present invention will be further described below in conjunction with the examples, but not any limitation of the present invention.

Embodiment one:

Tablet core prescription: by 1000 tablets

Composition of semi-permeable membrane coating solution:

Cellulose acetate 28g

PEG4000 4g

Acetone 1000mL, coating weight gain 8%

Preparation steps:

1) Weigh the sieved azithromycin and copovidone S-630 according to the prescription and mix evenly; then add the prescribed amount of citric acid and mix evenly; finally add the prescribed amount of talcum powder and magnesium stearate, and mix evenly;

2) tableting;

3) Coating, cellulose acetate-PEG4000 (7:1), acetone as solvent, until the weight of the tablet core increases by 8%;

4) Drilling, using laser or mechanical drilling to punch a small hole with a diameter of 0.8mm on one side of the coated tablet.

In vitro dissolution assay:

Intelligent dissolution apparatus (ZRS-8G, Tianjin Haiyida Technology Co., Ltd.), in accordance with the first method of the 2010 edition of the Chinese Pharmacopoeia release determination method, with 900mL water as the solvent, the speed is 100 rpm, at 0.5, 1, 2, Samples were taken at 4, 6, 8, 10, and 12 hours to measure the content of azithromycin, and the cumulative release rate was calculated.

The determination method of azithromycin content refers to the determination method of azithromycin content in the 2010 edition of Chinese Pharmacopoeia.

The in vitro dissolution curve of the obtained azithromycin osmotic pump controlled-release tablet is shown in Figure 1.

Comparative example one:

Azithromycin Generic Tablets

Calculated by 1000 pieces

Ketoprofen 50g

Lactose 69g

Magnesium stearate 1g

Preparation steps:

1) Weigh azithromycin and lactose that have passed through a 60-mesh sieve according to the prescription and mix evenly;

2) Add the prescribed amount of magnesium stearate, mix well, and press into tablets.

The in vitro release rate measurement is the same as in Example 1, and the in vitro release rate curve is shown in FIG. 1 .

Embodiment two:

Tablet core prescription: by 1000 tablets

Composition of semi-permeable membrane coating solution:

Cellulose acetate 36g

PEG4000 4g

Acetone 2000mL, coating weight gain 6%

Preparation steps:

1) Weigh the sieved azithromycin, copovidone S-630, and NaCl according to the prescription and mix evenly; then add the prescribed amount of citric acid and mix evenly; finally add the prescribed amount of talcum powder and magnesium stearate, and mix evenly;

2) tableting;

3) Coating, cellulose acetate-PEG4000 (9:1), acetone as solvent, until the weight of the tablet core increases by 6%;

4) Drilling, using laser or mechanical drilling to punch a small hole with a diameter of 0.8mm on one side of the coated tablet.

The in vitro dissolution test is as in Example 1. The in vitro dissolution curve of the obtained azithromycin osmotic pump controlled-release tablet is shown in FIG. 2 .

Ordinary tablets are as in Comparative Example 1.

Embodiment three:

Tablet core prescription: by 1000 tablets

Composition of semi-permeable membrane coating solution:

Cellulose acetate 56g

PEG4000 8g

Acetone 2000mL, coating weight gain 8%

Preparation steps:

1) Weigh the sieved azithromycin and copovidone S-630 according to the prescription and mix evenly; then add the prescribed amount of citric acid and mix evenly; finally add the prescribed amount of talcum powder and magnesium stearate, and mix evenly;

2) tableting;

3) Coating, cellulose acetate-PEG4000 (7:1), acetone as solvent, until the weight of the tablet core increases by 8%;

4) Drilling, using laser or mechanical drilling to punch a small hole with a diameter of 0.8mm on one side of the coated tablet.

The in vitro dissolution test is as in Example 1. The in vitro dissolution curve of the obtained azithromycin osmotic pump controlled-release tablet is shown in FIG. 3 .

Ordinary tablets are as in Comparative Example 1.

Embodiment four:

Tablet core prescription: by 1000 tablets

Drug-containing layer:

Boost layer:

Composition of semi-permeable membrane coating solution:

Cellulose acetate 28g

PEG4000 4g

Acetone 1000mL, coating weight gain 8%

Preparation steps:

1) Weigh the sieved azithromycin and copovidone S-630 according to the prescription amount, mix them evenly, then add the prescribed amount of citric acid and mix evenly, and finally add the prescribed amount of talcum powder and magnesium stearate to obtain the Drug layer powder, spare;

2) Weigh the sieved copovidone S-630 and citric acid according to the prescription quantity and mix evenly, add the prescription quantity of talcum powder and magnesium stearate to obtain the booster layer powder, and set aside;

3) The drug-containing layer powder and the booster layer powder are compressed twice to obtain a double-layer tablet core;

4) Coating, cellulose acetate-PEG4000 (7:1), acetone as solvent, until the weight of the tablet core increases by 8%;

5) Drilling, using laser or mechanical drilling to punch a small hole with a diameter of 0.8mm on one side of the coated tablet.

The in vitro dissolution test is as in Example 1. The in vitro dissolution curve of the obtained azithromycin osmotic pump controlled-release tablet is shown in FIG. 4 .

Ordinary tablets are as in Comparative Example 1.

Embodiment five:

Tablet core prescription: by 1000 tablets

Drug-containing layer:

Boost layer:

Composition of semi-permeable membrane coating solution:

Cellulose acetate 28g

PEG4000 4g

Acetone 1000mL, coating weight gain 5.5%

Preparation steps:

1) Weigh the sieved azithromycin and copovidone S-630 according to the prescription amount, mix them evenly, then add the prescribed amount of citric acid and mix evenly, and finally add the prescribed amount of talcum powder and magnesium stearate to obtain the Drug layer tablet core powder, spare;

2) Weigh the sieved copovidone S-630, citric acid, NaCl, and red iron oxide according to the prescription quantity and mix evenly, add the prescription quantity of talcum powder and magnesium stearate to obtain the booster layer tablet core powder ,spare;

3) The drug-containing layer powder and the booster layer powder are compressed twice to obtain a double-layer tablet core;

4) Coating, cellulose acetate-PEG4000 (7:1), acetone as solvent, until the weight gain of the tablet core is 5.5%;

5) Drilling, using laser or mechanical drilling to punch a small hole with a diameter of 0.8mm on one side of the coated tablet.

The in vitro dissolution test is as in Example 1. The in vitro dissolution curve of the obtained azithromycin osmotic pump controlled-release tablet is shown in FIG. 5 .

Ordinary tablets are as in Comparative Example 1.

Claims (10)

1. an azithromycin osmotic pump controlled release tablet, described azithromycin osmotic pump controlled release tablet is by label and be with foraminate semi permeability film coating to form, wherein, and based on the gross weight of label, the azithromycin that described label comprises 20-80wt%; The acid cosolvent of 5-50wt%; The pharmaceutically acceptable adjuvant of the skeletal matrix of 5-50wt% and 1-60wt%, described acid cosolvent is organic acid, mineral acid or its compositions.

2. azithromycin osmotic pump controlled release tablet according to claim 1, wherein, described label comprises 30-60wt%, preferably the azithromycin of 35-50wt%; 5-30wt%, the preferably acid cosolvent of 5-15wt%; 10-50wt%, preferably skeletal matrix and the pharmaceutically acceptable adjuvant of 1-50wt% of 20-50wt%.

3. azithromycin osmotic pump controlled release tablet according to claim 1 and 2, wherein, described acid cosolvent is to be selected from one or more in citric acid, tartaric acid, lactobionic acid, maleic acid, fumaric acid, Aspartic Acid.

4. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, described skeletal matrix is to be selected from one or more in ethyl cellulose, hyprolose, hypromellose, sodium carboxymethyl cellulose, polyvidone, Plasdone S-630, carbomer, acrylic resin, stearic acid and octadecanol.

5. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, described pharmaceutically acceptable adjuvant comprises one or more in binding agent, lubricant, opacifier, filler, coloring agent and osmotic pressure regulator, and wherein said binding agent is to be selected from one or more in starch slurry, polyvidone, hyprolose, hypromellose, methylcellulose, gelatin and Polyethylene Glycol; Described lubricant is to be selected from one or more in magnesium stearate, Pulvis Talci, micropowder silica gel and Polyethylene Glycol; Described opacifier is to be selected from one or more in titanium dioxide, Pulvis Talci and silicon dioxide; Described filler is to be selected from one or more in microcrystalline Cellulose, starch, dextrin, mannitol and calcium carbonate; Described coloring agent is red ferric oxide; Described osmotic pressure regulator is to be selected from one or more in sodium chloride, potassium chloride, lactose, mannitol.

6. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, the film-coated weightening finish of described semi permeability is the 3%-10% of label quality.

7. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, described semi permeability film coating comprises semipermeable membrane coating material, penetrating regulator and optional pharmaceutically acceptable plasticizer, and wherein said semipermeable membrane coating material is to be selected from one or more in cellulose acetate, CAP, acrylic resin and hydroxypropyl cellulose phthalate ester; Described penetrating regulator is to be selected from one or more in PEG series, polyvidone, copolyvidone and hyprolose; Described plasticizer is selected from phthalate.

8. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, based on the weight of osmotic pump controlled release tablet, in described azithromycin controlled release tablet, comprise: the azithromycin of 20-80wt%; The Plasdone S-630 of 5-50wt%; The citric acid of 5-50wt%; The cellulose acetate of 1-30wt%; The PEG4000 of 0.1-30wt%, preferably the weight ratio of cellulose acetate and PEG4000 is 9:1-5:1.

9. according to the azithromycin osmotic pump controlled release tablet one of claims 1 to 3 Suo Shu, wherein, described azithromycin osmotic pump controlled release tablet is monolayer or double-layer osmotic pump controlled-release tablet.

10. prepare in aforementioned claim 1 to 9 method for azithromycin osmotic pump controlled release tablet described in any one, the method comprises:

Granulate: first take respectively by recipe quantity the each component except lubricant that label each several part comprises, by its mix homogeneously, finally add lubricant and mix;

Tabletting;

Bag semipermeable membrane clothing;

Punching, adopting laser or mechanical punching mode to beat diameter in the one side or the multi-lateral of coated tablet is 0.2mm-1.2mm aperture.

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