HK1161971A1 - A capsule preparation containing tegafur, gimeracil and oteracil potassium - Google Patents

Abstract

The invention refers to a capsule preparation containing tegafur, gimeracil and potassium oxonate. The capsule preparation comprises the following components by weight parts: 20 parts of tegafur, 5-6 parts of gimeracil, 19-20 parts of potassium oxonate, 10-300 parts of lactose, and 0.9-5 parts of sodium dodecyl sulfate. According to the invention, the use level of the surfactant of sodium dodecylsulfate is greatly reduced on the premise of guaranteeing rapid dissolving-out of active components in the preparation, so that the irritation of the capsule preparation to the human gastrointestinaltract is decreased and the medicine compliance of a patient is increased.

Description

Capsule preparation containing tegafur, gimeracil and oteracil potassium

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a capsule preparation containing tegafur, gimeracil and oteracil potassium.

Background

Tegafur (FT, FT207) is one of pyrimidine anticancer drugs, is a prodrug of 5-fluorouracil (5-FU), and has an inhibitory effect on most solid tumors. Can interfere and block the biosynthesis of DNA, RHA and protein in vivo, thereby generating the anticancer effect. The basic research and clinical observation of medicine prove that the tegafur has small toxic and side effect, higher chemotherapy index, smaller influence on immunosuppressive action and relevant immune organs, and is a safe medicament which can be continuously used clinically. The product can be absorbed by gastrointestinal tract after oral administration, and the blood concentration reaches peak within 1-3 hr. The duration is longer than that of intravenous administration, so that the better treatment effect can be exerted. Is mainly used for gastric cancer, biliary tract cancer, rectal cancer, colon cancer, pancreatic cancer, liver cancer, breast cancer, lung cancer and head and neck cancer. In addition, has certain curative effect on preventing relapse and metastasis after operation. The most major adverse reactions of tegafur are digestive tract symptoms, bone marrow suppression, neurotoxicity reaction and the like. The product is fluorouracil derivative, has no antitumor effect in vitro, and has effect in vivo due to conversion into fluorouracil by liver. The effect of the composition is the same as that of fluorouracil, and the chemotherapy index is 2 times of that of fluorouracil.

Gimeracil (CDHP) and oteracil potassium (OXO) alone have no significant anti-cancer activity, and their combination with tegafur is intended to improve efficacy and reduce toxicity. The CDHP has the function of improving the anticancer effect of FT, when FT enters the body orally, the FT is firstly converted into 5-FU under the catalysis of liver P450 activating enzyme, then about 10 percent of 5-FU enters the intestinal tract and is phosphorylated under the catalysis of Orotate Ribosyltransferase (ORTC), and the other about 90 percent of 5-FU is converted into two active products of floxuridine triphosphate (FUTP) and deoxyfloxuridine monophosphate (FdUMP) under the catalysis of liver dihydropyrimidine dehydrogenase (DPD) to play the anticancer role. Thus, DPD is the major rate-limiting enzyme in 5-FU degradation, and maintenance of its plasma 5-FU levels is dependent on DPD activity. CDHP is a reversible inhibitor of DPD. By comparison, CDHP has 180 times of the effect of inhibiting DPD activity compared with uracil, so that the CDHP can effectively inhibit the degradation of 5-FU. Experiments prove that when CDHP and FT are matched at a ratio of 0.4: 1(M), the effective level of 5-FU in tumor tissues can be kept for more than 12 hours, and the toxic and side effects of intestinal tracts can not be increased. The main effect of oteracil potassium is to inhibit the activity of small intestine tissue ORTC. In the metabolic process of tegafur, about 10% of 5-FU enters intestinal tissues and is subjected to phosphorylation under the catalysis of orotate ribosyltransferase, and the process is considered to be a main cause of toxic and side effects in the intestinal tract. Another significant characteristic of OXO is that after being orally administered into the body, it is mostly distributed on the surface of small intestine mucosal cells, and only a very small part of it enters blood circulation, tumor tissues and other normal tissues. Thus, OXO primarily inhibits the phosphorylation of 5-FU in small intestinal tissues, and does not affect the activity of 5-FU in tumor tissues. When the ratio of OXO to FT (M) is 1: 1, the composition can not only keep higher tumor inhibition effect, but also greatly reduce the intestinal toxic and side effect.

Tegafur is slightly dissolved in water, gimeracil is slightly dissolved in water, oteracil potassium is slightly dissolved in water, but the medicine is required to be quickly dissolved and quickly take effect clinically, so that the medicine dissolution rate is required to be improved by adopting a proper formula and a proper process in the production of the preparation.

CN200910127355.6 discloses a tegafur capsule preparation and a preparation method thereof, the stability of tegafur is improved, however, the solubility of the drug is not improved, in order to ensure rapid dissolution, a large amount of surfactant is added, the minimum dosage reaches 10 mg/granule, the stimulation to gastrointestinal tract is large, and meanwhile, a pellet coating technology is adopted, and the workshop production process is complex.

Zl200410075803.x discloses a prescription and a preparation process of tegafur oral disintegrating tablet, which can cover the undesirable bitter taste of the drug, but the water solubility of the drug is not improved.

ZL200910266511.7 discloses a Tegafur granule, which is prepared by a method for preparing a cyclodextrin inclusion compound from active ingredients of a medicament so as to improve the dissolution rate and the bioavailability of the medicament, but the cyclodextrin inclusion process is complex, and the industrial production in a workshop is inconvenient.

ZL200910211359.2 discloses a tegafur dispersible tablet, wherein gimeracil and oteracil potassium can be released in the stomach before tegafur, so that oteracil potassium can better play a role in protecting the gastrointestinal tract, gimeracil can better play a role in coordinating with tegafur, the compliance of patients is improved, but a pellet coating technology is adopted in the process, and the production process of a workshop is complex.

Disclosure of Invention

The first purpose of the invention is to provide a novel capsule preparation containing tegafur, gimeracil and oteracil potassium.

After researching the prescription and the process of the existing tegafur capsule, the inventor unexpectedly finds that the dissolution rate of the active ingredients in the tegafur capsule preparation is still ideal after the dosage of the surfactant sodium dodecyl sulfate in the tegafur capsule preparation is greatly reduced. Therefore, the invention provides the following technical scheme:

a capsule preparation containing tegafur, gimeracil and oteracil potassium comprises the following components in parts by weight:

preferably, the capsule preparation consists of the following components in parts by weight:

in order to further improve the dissolution rate of the active ingredients in the preparation, the second object of the invention is to provide a method for preparing a tegafur capsule preparation by using the above formula, which comprises the following steps:

(1) preparing 1-15% sodium dodecyl sulfate aqueous solution from sodium dodecyl sulfate;

(2) sieving tegafur, gimeracil, potassium oteracil and lactose with 80-200 mesh sieve, mixing well, adding the sodium dodecyl sulfate aqueous solution, granulating, drying at 40-70 deg.C, grading with 12-30 mesh sieve, and filling into capsules.

Compared with the prior art, the tegafur and gimeracil Okayama capsule preparation has the following advantages and remarkable progress:

(1) on the premise of ensuring that active ingredients in the preparation are quickly dissolved out, the dosage of a surfactant, namely sodium dodecyl sulfate, is greatly reduced, so that the irritation of the sodium dodecyl sulfate to the gastrointestinal tract of a human body is reduced, the problems in the prior art are well solved, and the medication compliance of a patient is improved.

(2) The dissolution rate of the active ingredients in the preparation is higher, and the preparation process is simple and is suitable for industrial production.

Detailed Description

It is to be understood that other embodiments and modifications which are obvious to those skilled in the art in the practice of the invention and which do not depart from the scope and spirit of the invention as described above are deemed to be within the scope and spirit of the invention. Therefore, it should not be understood that the scope of the claims is limited to the following examples.

Example 1 preparation of tegafur Capsule

The preparation process comprises the following steps: sieving the raw materials and the auxiliary materials with a 100-mesh sieve, uniformly mixing, adding a 5% SDS aqueous solution, granulating, drying at 60 ℃, grading with a 20-mesh sieve, and filling capsules to obtain the capsule.

Example 2 preparation of tegafur Capsule

The preparation process comprises the following steps: sieving the raw materials and the auxiliary materials with a 100-mesh sieve, uniformly mixing, adding 10% SDS aqueous solution, granulating, drying at 60 ℃, grading with a 12-mesh sieve, and filling capsules to obtain the capsule.

Example 3 preparation of tegafur Capsule

The preparation process comprises the following steps: sieving the raw materials and the auxiliary materials with a 200-mesh sieve, uniformly mixing, adding a 3% SDS aqueous solution, granulating, drying at 40 ℃, grading with a 30-mesh sieve, and filling capsules to obtain the capsule.

Example 4 preparation of tegafur Oak Capsule

The preparation process comprises the following steps: sieving raw materials and adjuvants with 80 mesh sieve, mixing, adding 10% SDS water solution, granulating, drying at 70 deg.C, sieving with 20 mesh sieve, and filling into capsule.

Example 5 preparation of tegafur Oak Capsule

The preparation process comprises the following steps: sieving the raw materials and the auxiliary materials with a 100-mesh sieve, uniformly mixing, adding a 5% SDS aqueous solution, granulating, drying at 60 ℃, grading with a 20-mesh sieve, and filling capsules to obtain the capsule.

Comparative example 1 preparation of tegafur capsules

The preparation process comprises the following steps: sieving the raw materials and adjuvants with 100 mesh sieve, mixing, adding appropriate amount of water solution, granulating, drying at 60 deg.C, grading with 20 mesh sieve, and filling into capsule.

Comparative example 2 preparation of tegafur capsules

The preparation process comprises the following steps: sieving the raw materials and adjuvants with 100 mesh sieve, mixing, adding 2.5% SDS water solution, granulating, drying at 60 deg.C, sieving with 20 mesh sieve, and filling into capsule.

Comparative example 3 preparation of tegafur capsules

The preparation process comprises the following steps: sieving the raw materials and adjuvants with 100 mesh sieve, mixing, adding water solution, granulating, drying at 60 deg.C, grading with 20 mesh sieve, and filling into capsule.

Example 5 dissolution assay of tegafur capsules

Adopting a dissolution determination method (XC first method which is an appendix of the second part of the 2010 edition of the Chinese pharmacopoeia), taking the capsules in the examples 1-5 and the comparative example, taking 0.1mol/L hydrochloric acid aqueous solution as a dissolution medium, operating according to a method at the rotating speed of 50r/min and the temperature of 37 +/-0.5 ℃, sucking 5ml of dissolution liquid at 15min, simultaneously supplementing an equal amount of dissolution medium, filtering the dissolution liquid by using a filter membrane of 0.45um, determining the dissolution rate of the tegafur capsule by adopting a high performance liquid chromatography, wherein the limit is 85% of a marked amount, and determining the dissolution result shown in the following table.

Dissolution determination of Epigallo capsules

The dissolution rate of each embodiment in 15min is more than 95%, which shows that when the dosage of SDS is 0.9-5 mg/grain, tegafur, gimeracil and oteracil potassium can be dissolved out quickly, so that a good treatment effect can be achieved.

Under the same conditions, the dissolution of comparative examples 1 and 2 is unqualified and is lower than 85 percent, which indicates that the dosage of the sodium dodecyl sulfate is too small to influence the dissolution of the medicine. Comparative example 3 the same amount of SDS added as in example 2, but the dissolution was poor, which indicates that the dissolution property of the formulation can be improved by adding sodium dodecyl sulfate as an aqueous solution to the material at the end of the process of preparing the tablet.

Claims (1)

1. A capsule preparation containing tegafur, gimeracil and oteracil potassium is characterized in that: the composition is prepared from the following components in parts by weight:

tegafur 20 parts

Gimeracil 5.8 parts

19.6 parts of potassium oxiracetam

10-300 parts of lactose

0.9-3 parts of sodium dodecyl sulfate

The preparation process of the capsule preparation comprises the following steps:

(1) preparing 1-15% sodium dodecyl sulfate aqueous solution from sodium dodecyl sulfate;

(2) sieving tegafur, gimeracil, potassium oteracil and lactose with 80-200 mesh sieve, mixing well, adding the sodium dodecyl sulfate aqueous solution, granulating, drying at 40-70 deg.C, grading with 12-30 mesh sieve, and filling into capsules.