CN109364033B - Mercaptopurine quartering chewable tablet and preparation method thereof - Google Patents
Mercaptopurine quartering chewable tablet and preparation method thereof Download PDFInfo
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- CN109364033B CN109364033B CN201811402573.1A CN201811402573A CN109364033B CN 109364033 B CN109364033 B CN 109364033B CN 201811402573 A CN201811402573 A CN 201811402573A CN 109364033 B CN109364033 B CN 109364033B
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61K9/20—Pills, tablets, discs, rods
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- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
The invention relates to a mercaptopurine tablet which is composed of mercaptopurine, polyethylene glycol 6000, a bonding agent, a disintegrating agent, a filling agent and a lubricating agent. The invention mixes polyethylene glycol 6000 and sorbitol, then mixes them with mercaptopurine, heats them to melt, then quickly condenses them to form solid dispersoid, screens them and pulverizes them, then mixes the pulverized particles with disintegrant and lubricant, then directly tabletting. The mercaptopurine is prepared into solid dispersion and then is directly tableted, and compared with the common wet granulation and tabletting process, the risk that the mercaptopurine is easy to stick and impact in the production process is reduced. Meanwhile, patients can directly chew for taking without water, so that the convenience and the compliance of the patients for taking medicine are greatly improved, and the four-quarter chewing tablet is favorable for realizing accurate administration and improving the taking compliance of children patients.
Description
Technical Field
The invention relates to the technical field of medicinal preparations, in particular to a mercaptopurine quartering chewable tablet and a preparation method thereof.
Background
Mercaptopurine belongs to a cell cycle specific drug inhibiting a purine synthesis pathway, has a chemical structure similar to that of purine, and is one of basic chemical substances constituting DNA. In vivo, mercaptopurine is converted intracellularly into a substance that interferes with the production of new DNA, and can prevent cell division, thereby slowing the progression of acute lymphocytic leukemia. Mercaptopurine is not completely absorbed orally and has individual difference, the average value of in vivo absorption is about 50% of the administration dosage, and factors influencing the absorption are not clear at all. Mercaptopurine is slightly soluble in water and ethanol and practically insoluble in diethyl ether. Mercaptopurine is easily soluble in alkaline aqueous solution, but is unstable, slowly hydrolyzes, and turns into black color when exposed to the light in the air. Mercaptopurine has been widely used at home and abroad, and is an important medicine for maintaining and treating acute lymphocytic leukemia. In the prior art, mercaptopurine is generally prepared into tablets, and has high stability and convenient carrying. However, mercaptopurine is easy to absorb moisture, the sticking phenomenon is easy to generate in the industrial production process, the dosage is large, and the side effects are more. The mercaptopurine quartering chewable tablet helps to overcome the problems, improves the compliance of patients, is convenient to flexibly adjust the administration dosage according to the actual condition of the patients, and is beneficial to individualized and accurate treatment of the administration dosage.
Disclosure of Invention
The invention aims to solve the sticking phenomenon in the preparation process of the tablet, improve the compliance of patients, facilitate flexible adjustment of the administration dosage according to the actual condition of the patients and facilitate individual precise treatment of the administration dosage.
The second purpose of the invention is to provide a mercaptopurine quartering chewable tablet and a preparation method thereof, and the purpose is to provide a preparation of the mercaptopurine quartering chewable tablet, which meets the marketization requirement of children patients and reduces adverse reactions caused by improper dosage.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted: the mercaptopurine quartering chewable tablet is prepared by uniformly mixing and melting mercaptopurine, polyethylene glycol 6000 and sorbitol, preparing into a solid dispersion, and uniformly mixing and tabletting with microcrystalline cellulose, a flavoring agent and other pharmaceutically acceptable auxiliary materials.
Researches find that the ratio of the carrier polyethylene glycol 6000 to sorbitol and the ratio of the raw material mercaptopurine in the carrier polyethylene glycol 6000 to sorbitol have obvious influence on compressibility, so that the influence of different ratios of the raw material to the carrier on flowability and compressibility is respectively considered; the process comprises the following steps: heating mercaptopurine, polyethylene glycol 6000 and sorbitol to be molten, and rapidly cooling and solidifying under violent stirring; sieving with 30 mesh sieve, and pulverizing; drying; adding the microcrystalline cellulose, aspartame, disintegrant and lubricant according to the prescription amount, uniformly mixing, and tabletting by using a four-part punch. The results are shown in Table 1.
TABLE 1 Effect of Carrier to raw Material ratio on compressibility and flowability
The mercaptopurine quartering chewable tablet comprises polyethylene glycol 6000 and sorbitol in a ratio of 1:1-1: 2.
The weight ratio of the mercaptopurine of the formula to the composition polyethylene glycol 6000 and sorbitol is 1:3-1: 6.
A mercaptopurine quartering chewable tablet is prepared by using a solid dispersion with the moisture content of less than 2%.
The mercaptopurine quartering chewable tablet comprises 8% -12% of raw materials; the preparation method comprises the following steps: heating mercaptopurine, polyethylene glycol 6000 and sorbitol to be molten, and rapidly cooling and solidifying under violent stirring; sieving with 30 mesh sieve, and pulverizing; drying; adding microcrystalline cellulose, aspartame, a disintegrating agent and a lubricating agent according to the prescription amount, uniformly mixing, and tabletting by using a quartering punch, wherein the weight of the tablet is controlled to be 0.60g-0.65 g.
The disintegration agent is sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose and other pharmaceutically acceptable super disintegration agents.
The thiopurine quartering chewable tablet comprises magnesium stearate, silicon dioxide, talcum powder and other pharmaceutically acceptable lubricants.
At present, the existing mercaptopurine is a conventional tablet, the specification of the conventional mercaptopurine is large, the conventional mercaptopurine is not matched with the specification of clinical medication for children, and the accurate regulation of the clinical dosing according to the weight, the illness state, the tolerance condition of the body and the like of an infant patient is difficult to realize. In addition, wet granulation and tabletting are adopted in the preparation process of the medicine, so that the medicine is easy to stick and dash, the process is complex and the cost is high. The clinical administration of patients is seriously affected, especially patients with dysphagia such as the elderly and children.
Through research, the inventor develops a mercaptopurine quartering tablet by repeatedly improving various auxiliary materials and the dosage thereof and strictly controlling parameters of various process links in the preparation process, wherein the tablet weight is 0.60-0.65 g, and the weight of mercaptopurine contained in each tablet is 48-72 mg. The content of each tablet can be controlled to be 12-16 mg after the four-division, so that the administration dosage can be flexibly adjusted according to the actual condition of a patient, and the individual accurate treatment of the administration dosage is facilitated.
Meanwhile, the mercaptopurine tablets are easy to stick and impact in the preparation process, and the preparation process is complex and the equipment cost is high by the conventional method;
in view of the above, the present application also provides a mercaptopurine quartering chewable tablet and a preparation method thereof. The tablet prepared by the semi-dry type granule tabletting method can improve the bioavailability of the medicine in vivo and reduce the side effect of the medicine, and simultaneously, the compliance and the clinical curative effect of a patient can be improved by four-part tablet.
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In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a front view of a 13mm quad punch;
figure 2 is a side view of a 13mm quarter punch.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Specifically, the invention is realized by the following technical means: a preparation method of mercaptopurine quartering chewable tablets comprises the following steps: the preparation method comprises the following steps: heating mercaptopurine, polyethylene glycol 6000 and sorbitol to be molten, and rapidly cooling and solidifying under violent stirring; sieving with 30 mesh sieve, and pulverizing; drying; adding microcrystalline cellulose, aspartame, a disintegrating agent and a lubricating agent according to the prescription amount, uniformly mixing, and tabletting by using a quartering punch, wherein the weight of the tablet is controlled to be 0.60g-0.65 g.
The disintegrating agent is one of sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose, and the lubricant is one of magnesium stearate, silicon dioxide and talcum powder. Wherein the ratio of the polyethylene glycol 6000 to the sorbitol is 1:1-1:2, and the weight ratio of the mercaptopurine to the polyethylene glycol 6000 and the sorbitol is 1:3-1: 6.
The present invention is described in detail below with reference to several examples.
Detailed Description
Example 1
| Name (R) | Single dose (mg/tablet) | Ratio (%) |
| Mercaptopurine | 50 | 7.7 |
| Polyethylene glycol 6000 | 97.5 | 15 |
| Sorbitol | 195 | 30 |
| Microcrystalline cellulose | 252.2 | 38.8 |
| Aspartame | 9.75 | 1.5 |
| Sodium carboxymethyl starch | 3.25 | 5 |
| Magnesium stearate | 0.65 | 1 |
| Total of | 650 | 100 |
The preparation steps are as follows:
(a) sieving polyethylene glycol 6000 and sorbitol with 60 mesh sieve, respectively, and heating to melt;
(b) adding mercaptopurine, and rapidly cooling and solidifying under the condition of vigorous stirring;
(c) sieving with 30 mesh sieve, and pulverizing; drying to water content of less than 2%;
(d) adding microcrystalline cellulose, aspartame, carboxymethyl starch sodium as disintegrant and magnesium stearate as prescription amount, mixing, and tabletting with four-part punch.
Example 2
| Name (R) | Single dose (mg/tablet) | Ratio (%) |
| Mercaptopurine | 78 | 12 |
| Polyethylene glycol 6000 | 97.5 | 15 |
| Sorbitol | 195 | 30 |
| Microcrystalline cellulose | 230.7 | 35.5 |
| Aspartame | 9.75 | 1.5 |
| Sodium carboxymethyl starch | 3.25 | 5 |
| Magnesium stearate | 0.65 | 1 |
| Total of | 650 | 100 |
The preparation steps are as follows:
(a) sieving polyethylene glycol 6000 and sorbitol with 60 mesh sieve, respectively, and heating to melt;
(b) adding mercaptopurine, and rapidly cooling and solidifying under the condition of vigorous stirring;
(c) sieving with 30 mesh sieve, and pulverizing; drying to water content of less than 2%;
(d) adding microcrystalline cellulose, aspartame, carboxymethyl starch sodium as disintegrant and magnesium stearate as prescription amount, mixing, and tabletting with four-part punch.
Example 3
| Name (R) | Single dose (mg/tablet) | Ratio (%) |
| Mercaptopurine | 65 | 10 |
| Polyethylene glycol 6000 | 97.5 | 15 |
| Sorbitol | 195 | 30 |
| Microcrystalline cellulose | 243.7 | 37.5 |
| Aspartame | 9.75 | 1.5 |
| Sodium carboxymethyl starch | 3.25 | 5 |
| Magnesium stearate | 0.65 | 1 |
| Total of | 650 | 100 |
The preparation steps are as follows:
(a) sieving polyethylene glycol 6000 and sorbitol with 60 mesh sieve, respectively, and heating to melt;
(b) adding mercaptopurine, and rapidly cooling and solidifying under the condition of vigorous stirring;
(c) sieving with 30 mesh sieve, and pulverizing; drying to water content of less than 2%;
(d) adding microcrystalline cellulose, aspartame, carboxymethyl starch sodium as disintegrant and magnesium stearate as prescription amount, mixing, and tabletting with four-part punch.
Example 4
| Name (R) | Single dose (mg/tablet) | Ratio (%) |
| Mercaptopurine | 60 | 10 |
| Polyethylene glycol 6000 | 90 | 15 |
| Sorbitol | 180 | 30 |
| Microcrystalline cellulose | 225 | 37.5 |
| Aspartame | 9 | 1.5 |
| Sodium carboxymethyl starch | 30 | 5 |
| Magnesium stearate | 6 | 1 |
| Total of | 600 | 100 |
The preparation steps are as follows:
(a) sieving polyethylene glycol 6000 and sorbitol with 60 mesh sieve, respectively, and heating to melt;
(b) adding mercaptopurine, and rapidly cooling and solidifying under the condition of vigorous stirring;
(c) sieving with 30 mesh sieve, and pulverizing; drying to water content of less than 2%;
(d) adding microcrystalline cellulose, aspartame, carboxymethyl starch sodium as disintegrant and magnesium stearate as prescription amount, mixing, and tabletting with four-part punch.
Example 5
| Name (R) | Single dose (mg/tablet) | Ratio (%) |
| Mercaptopurine | 65 | 10 |
| Polyethylene glycol 6000 | 97.5 | 15 |
| Sorbitol | 195 | 30 |
| Microcrystalline cellulose | 243.7 | 37.5 |
| Aspartame | 9.75 | 1.5 |
| Sodium carboxymethyl starch | 3.25 | 5 |
| Magnesium stearate | 0.65 | 1 |
| Total of | 650 | 100 |
(a) Sieving polyethylene glycol 6000 and sorbitol with 60 mesh sieve, respectively, and heating to melt;
(b) adding mercaptopurine, and rapidly cooling and solidifying under the condition of vigorous stirring;
(c) sieving with 30 mesh sieve, and pulverizing; drying to water content of 4%;
(d) adding microcrystalline cellulose, aspartame, carboxymethyl starch sodium as disintegrant and magnesium stearate as prescription amount, mixing, and tabletting with four-part punch.
In addition, the mercaptopurine quartering chewable tablets provided in other examples were used for carrying out the above experiments, and the results are substantially the same as those of example 4, and thus are not repeated.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (4)
1. The mercaptopurine chewable tablet is characterized in that mercaptopurine, polyethylene glycol 6000 and sorbitol are prepared into a solid dispersion, then the solid dispersion is mixed with microcrystalline cellulose, aspartame, a disintegrating agent and a lubricant, and the mixture is tabletted by a four-scored die through a direct tabletting process, wherein the ratio of the polyethylene glycol 6000 to the sorbitol is 1:1-1:2, the weight ratio of the mercaptopurine to the combination of the polyethylene glycol 6000 and the sorbitol is 1: 4-1: 6.
2. the mercaptopurine chewable tablet of claim 1 wherein the solid dispersion is prepared by a process comprising the steps of: heating polyethylene glycol 6000 and sorbitol to melt, adding mercaptopurine, mixing, rapidly cooling and solidifying under vigorous stirring, sieving with 30 mesh sieve, pulverizing, and drying until the water content is less than 2%.
3. The mercaptopurine chewable tablet of claim 1 wherein the tablet weight is from 0.60g to 0.65 g.
4. The mercaptopurine chewable tablet of claim 1 wherein the disintegrant is selected from sodium carboxymethyl starch, crospovidone, low substituted hydroxypropyl cellulose and the lubricant is selected from magnesium stearate, silicon dioxide, talc.
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|---|---|---|---|
| CN201811402573.1A CN109364033B (en) | 2018-11-23 | 2018-11-23 | Mercaptopurine quartering chewable tablet and preparation method thereof |
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| CN201811402573.1A CN109364033B (en) | 2018-11-23 | 2018-11-23 | Mercaptopurine quartering chewable tablet and preparation method thereof |
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| CN109364033B true CN109364033B (en) | 2021-10-01 |
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| CN103222964B (en) * | 2013-01-29 | 2014-10-08 | 青岛大学 | Orlistat oral preparation and preparation method thereof |
| CN108553437A (en) * | 2018-06-08 | 2018-09-21 | 姚静 | One kind passing through mercaptopurine chewable tablets and preparation method thereof made from ion exchange technique |
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