CN104224742A - Thiamphenicol enteric-coated tablets - Google Patents

Abstract

The application relate to thiamphenicol enteric-coated tablets. Thiamphenicol is firstly prepared into an inclusion compound, and then the inclusion compound is prepared into enteric-coated tablets.

Description

Thiamphenicol enteric-coated tablets

technical field

The present application relates to an enteric-coated tablet, specifically, a thiamphenicol inclusion compound enteric-coated tablet.

Background technique

Thiamphenicol English/Latin name: Thiamphenicol, alias thiamphenicol, thiamphenicol chloramphenicol. This product is white crystalline powder; odorless.

Thiamphenicol is a synthetic broad-spectrum antibiotic and a substitute for chloramphenicol. Its antibacterial effect in vivo is stronger than that of chloramphenicol, but its toxicity is less than that of chloramphenicol. Thiamphenicol has poor water solubility, and its dosage form and clinical application are limited.

Thiamphenicol acts by inhibiting bacterial protein synthesis, mainly reversibly binding to the 50s subunit of the bacterial 70s ribosome, inhibiting peptidyltransferase, thereby specifically preventing aminoacyl-tRNA from interacting with the ribosome Receptor binding inhibits the elongation of the peptide chain and prevents bacterial protein synthesis. The two have the same antibacterial spectrum, have strong antibacterial power against all Gram-positive bacteria and negative bacteria, and are used for a variety of bacterial infections such as: Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis, golden yellow Staphylococcus, Streptococcus pyogenes, Streptococcus viridans, Group B hemolytic streptococcus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhi, Salmonella paratyphi, Shigella, fragilis Anaerobic bacteria such as Bacteroides. Documents record that long-term extensive use of thiamphenicol has no serious adverse reactions, so it is widely used clinically, mainly for the treatment of various surface infections, biliary tract infections, urinary tract infections, respiratory tract infections, WeberChristian disease, etc.

In many countries, thiamphenicol is mainly used in veterinary medicine, but in China and Italy, the antibiotic can also be used in the treatment of human diseases. In Brazil, thiamphenicol is also widely used.

At present, thiamphenicol mainly has dosage forms such as tablets, capsules, and injections for clinical use. These dosage forms have poor dissolution rate in the gastrointestinal tract and low bioavailability.

Contents of the invention

In order to solve the shortcomings of low bioavailability and poor targeting of existing thiamphenicol preparations, the present invention invents thiamphenicol inclusion compound enteric-coated tablets.

The clathrate has the following advantages: mask bad odor and reduce irritation; increase drug dissolution rate and bioavailability; improve drug stability.

The applicant found that the present preparation of thiamphenicol as an inclusion compound, combined with specific excipients to prepare enteric-coated tablets, has the advantages of high stability, fast disintegration speed and high bioavailability.

The invention provides a thiamphenicol preparation, wherein the active ingredient is thiamphenicol.

The invention provides a thiamphenicol preparation, wherein the preparation is an enteric-coated tablet.

The invention provides an enteric-coated tablet of thiamphenicol, wherein the active ingredient is thiamphenicol.

The invention provides an enteric-coated tablet of thiamphenicol, which comprises thiamphenicol, a filler, a binder, a disintegrant, a lubricant and an enteric coating material.

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription of thiamphenicol inclusion compound tablet core:

Enteric coating prescription:

Polyvinyl phthalate 5 copies Cellulose acetate trimellitate 12 copies 85% ethanol Appropriate amount talcum powder 5 copies

In this application, specific excipients were selected to prepare thiamphenicol inclusion compound enteric-coated tablets. Wherein the disintegrating agent is a composition of hydroxypropyl starch and sodium alginate, the weight ratio of the two is 3.5:11, and the enteric coating material is a composition of polyvinyl alcohol phthalate and cellulose acetate trimellitate, two The weight ratio is 5:12. Experiments have proved that not any conventional pharmaceutical excipients are suitable for the preparation of thiamphenicol inclusion compound enteric-coated tablets. The effects of other aspects are far better than the thiamphenicol inclusion compound enteric-coated tablets prepared by other excipients.

The thiamphenicol inclusion compound includes an active ingredient and an inclusion material, the active ingredient is thiamphenicol, and the inclusion material is α-cyclodextrin. The weight ratio of the active ingredient to the inclusion material is 1.5:4.2. Experiments have shown that the thiamphenicol inclusion compound prepared by β-cyclodextrin, hydroxy β-cyclodextrin, and hydroxypropyl β-cyclodextrin is far inferior to that in terms of disintegration speed, stability, and dissolution rate. Inclusion compound prepared from α-cyclodextrin.

Effects of different inclusion materials on thiamphenicol inclusion complex

inclusion material Dissolving speed (min) stability inclusion rate α-cyclodextrin 6 good 97% β-cyclodextrin 15 generally 86% Hydroxy beta-cyclodextrin 14 generally 88% Hydroxypropyl beta-cyclodextrin 17 generally 83%

The test method refers to the method stipulated in the second part of the Chinese Pharmacopoeia of the 2010 edition.

The preparation method of thiamphenicol inclusion compound comprises:

(1) In water or aqueous ethanol medium, react thiamphenicol with α-cyclodextrin in a certain proportion, filter the resulting solution through a microporous membrane until clarified, and separate the clathrate from the mixture; or

(2) in solid form, reacting thiamphenicol with α-cyclodextrin; or

(3) Thiamphenicol reacts with α-cyclodextrin for high-energy grinding.

The measurements in the present invention are all by weight.

Embodiment 1 prescription

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies disintegrant 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

Wherein the disintegrant is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11

Preparation:

1. Prepare thiamphenicol inclusion compound according to the following method:

(1) In water or aqueous ethanol medium, react thiamphenicol with α-cyclodextrin in a certain proportion, filter the resulting solution through a microporous membrane until clarified, and separate the clathrate from the mixture; or

(2) in solid form, reacting thiamphenicol with α-cyclodextrin; or

(3) Thiamphenicol reacts with α-cyclodextrin for high-energy grinding.

2. Preparation of thiamphenicol inclusion compound tablet core: the thiamphenicol inclusion compound is pulverized through a 100-mesh sieve, and the remaining auxiliary materials are pulverized through an 80-mesh sieve; Magnesium acid is excluded), starch slurry (10%) is granulated, granulated with a 18-mesh sieve, and dried at 40°C. Add the prescribed amount of magnesium stearate, mix evenly, pass through a 18-mesh sieve, measure the content of the main drug in the granules, determine the weight of the tablet, and compress the tablet to get final product.

3. Enteric-coating: dissolve the polyvinyl alcohol phthalate and cellulose acetate trimellitate in 85% ethanol to prepare a 5% solution of polyvinyl alcohol phthalate and cellulose acetate trimellitate. Grinding the talc powder, adding it to a solution of 5% polyvinyl alcohol phthalate and cellulose acetate trimellitate, passing through a 120-mesh sieve for use as an enteric coating solution.

Put the thiamphenicol inclusion complex tablet core in the coating pot, spray the above enteric coating solution, control the temperature of the pot at about 35°C, and finish the spraying within 4 hours.

Example 2

Thoroughly grind the thiamphenicol and α-cyclodextrin described in Example 1 in 50% ethanol until a uniform paste is formed, and a white powder is obtained after vacuum drying. Mycin increased by 13 times.

Comparative Example 1

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies Hydroxypropyl starch 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies

Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

The preparation method is the same as in Example 1.

Comparative Example 2

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies sodium alginate 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

The preparation method is the same as in Example 1.

Comparative Example 3

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies

Starch slurry (10%) 25 copies hypromellose 10 copies Hydroxypropyl Starch: Sodium Alginate 1:1 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

The preparation method is the same as in Example 1.

Comparative Example 4

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 100 copies Mannitol 150 copies Starch slurry (10%) 25 copies hypromellose 10 copies disintegrant 25 copies Magnesium stearate 10 copies

Enteric coating prescription:

Polyvinyl phthalate 40 copies Cellulose acetate trimellitate 40 copies 85% ethanol Appropriate amount talcum powder 15 copies

Wherein the disintegrant is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11

Preparation method is the same as embodiment 1

Comparative Example 5

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies lactose 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies disintegrant 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

Wherein the disintegrant is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11

Preparation method is the same as embodiment 1

Comparative Example 6

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription for thiamphenicol tablets:

Thiamphenicol 150 copies Mannitol 180 copies

Starch slurry (10%) 25 copies hypromellose 10 copies disintegrant 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount talcum powder 15 copies

Wherein the disintegrant is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11

Preparation method is the same as embodiment 1

Comparative Example 7

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

The application provides an enteric-coated tablet of thiamphenicol, which includes:

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies Croscarmellose Sodium 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Polyvinyl phthalate 25 copies Cellulose acetate trimellitate 60 copies 85% ethanol Appropriate amount

talcum powder 15 copies

Preparation method is the same as embodiment 1

Comparative Examples 1-7 adjusted the auxiliary materials or consumption used in Example 1, and the specific changes are as follows:

group Changes Example 1 Comparative Example 1 Disintegrant only hydroxypropyl starch Comparative Example 2 The disintegrant is sodium alginate only Comparative Example 3 Disintegrant hydroxypropyl starch: sodium alginate is 1:1 Comparative Example 4 The dosage of each ingredient changes Comparative Example 5 filler is lactose Comparative Example 6 Thiamphenicol is not an inclusion complex Comparative Example 7 The disintegrant is croscarmellose sodium

Effects of different enteric coating materials on thiamphenicol enteric-coated tablets

Test method: The dissolution rates of thiamphenicol enteric-coated tablets prepared from different enteric-coating materials were measured in simulated gastric juice environment and simulated intestinal environment, respectively. The results are shown in Table 1.

prescription:

Thiamphenicol inclusion compound: thiamphenicol:α-cyclodextrin is 1.5:4.2

Prescription of thiamphenicol inclusion compound tablet core:

Thiamphenicol inclusion complex 150 copies Mannitol 180 copies Starch slurry (10%) 25 copies hypromellose 10 copies disintegrant 14.5 servings Magnesium stearate 8 servings

Enteric coating prescription:

Enteric coating material See Table 1 below 85% ethanol Appropriate amount talcum powder 15 copies

Wherein the disintegrant is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11

Table 1

As can be seen from the data in Table 1, only the composition of polyvinyl alcohol phthalate and cellulose acetate trimellitate that adopts a weight ratio of 5:12 is used as the group 1 enteric-coated tablet of the enteric coating material (i.e. Example 1 ) is almost insoluble in the simulated gastric juice environment, and can be almost completely dissolved in the simulated intestinal environment; while the enteric-coated tablets prepared by other enteric coating materials have a large dissolution rate in the simulated gastric juice environment, which cannot make the tablet pass through the stomach safely And then disintegrated in the intestinal tract. Therefore, the enteric-coated tablet of the present application uses specific enteric-coated auxiliary materials, and other types of enteric-coated auxiliary materials are not suitable for preparing thiamphenicol inclusion compound enteric-coated tablets.

Stability test of thiamphenicol enteric-coated tablets

The influencing factors were investigated on the appearance, dissolution rate, content and disintegration time of the enteric-coated tablets of Example 1 and Comparative Examples 1-7.

(1) High temperature test: Take the samples of Example 1 and Comparative Examples 1-7 and spread them on a petri dish in an appropriate amount, and place them in a thermostat at 60°C for 10 days. During this period, on days 0, 5, and 10, respectively Take samples for measurement,

The measurement results are shown in Table 2.

(2) High-humidity test: Take a proper amount of samples and spread them on a petri dish, and place them at 25°C for 10 days under the condition of relative humidity RH90%±5%. The measurement results are shown in Table 2.

(3) In the strong light irradiation test, take an appropriate amount of samples and lay them flat on a petri dish, and place them in a light cabinet under the condition of 4500Lx±500Lx for 10 days. The results are shown in Table 2.

Table 2. Stability of enteric-coated tablets in various examples under high temperature, high humidity and strong light

It can be seen from the experimental data in Table 2 that when the dosage of each component is exactly the same, no matter whether the type of excipients is changed, or the type of excipients is not changed but the proportion of the components is changed, the prepared thiamphenicol sausage Compared with Example 1, the stability of dissolved tablets was significantly reduced. Under the condition that the components of the auxiliary materials and the weight ratio did not change, the dosage of each component changed, and the stability of the prepared thiamphenicol enteric-coated tablets was compared with that of Example 1. 1 is significantly lower. The above experimental data shows that the thiamphenicol enteric-coated tablets prepared by using specific excipients and dosages according to the present invention have unexpected excellent stability effects.

Claims (4)

1. A thiamphenicol preparation, wherein the active ingredient is thiamphenicol. 2. The thiamphenicol preparation as claimed in claim 1, wherein the preparation is an enteric-coated tablet. 3. The thiamphenicol preparation as claimed in claim 2, wherein the enteric-coated tablet active ingredient is thiamphenicol. 4. An enteric-coated tablet of thiamphenicol, which includes thiamphenicol, filler, binding agent, disintegrant, lubricant and enteric coating material, Prescription of thiamphenicol inclusion compound tablet core: Enteric coating prescription: Polyvinyl phthalate 5 copies Cellulose acetate trimellitate 12 copies 85% ethanol Appropriate amount talcum powder 5 copies The above-mentioned disintegrating agent is a composition of hydroxypropyl starch and sodium alginate, and the weight ratio of the two is 3.5:11.