HK1112672B

HK1112672B - Vinorelbine soft capsule, preparing method and use thereof

Info

Publication number: HK1112672B
Application number: HK08107774.9A
Authority: HK
Inventors: 锺慧娟
Original assignee: 江苏豪森药业集团有限公司
Filing date: 2008-07-15
Publication date: 2012-07-20

Abstract

The present invention relates to an improved formulation of Changchun Ruibin soft capsules, which contain Changchun Ruibin or Changchun Ruibin tartrate, ethanol and polyethylene glycol, without water and glycerol. The soft capsules of the present invention solve the problem of phlebitis during intravenous administration of Changchun Ruibin, simplify the prescription of the soft capsule filling composition, facilitate industrial manufacturing, improve the stability of the formulation, and reduce the adverse effects of excipients on patients.

Description

Vinorelbine soft capsule, preparation method and application thereof

Technical Field

The invention relates to a capsule preparation, in particular to a soft capsule containing vinorelbine tartrate.

Background

Vinorelbine is an antitumor drug of vinblastine for inhibiting cell division, directly acts on the dynamic balance of tubulin/microtubule, can inhibit the polymerization of tubulin, disintegrate microtubule in division phase, affect axon microtubule only at high concentration, have lower effect on tubulin spiralization than vincristine, and cause cell death in interphase or anaphase of division by blocking mitosis of G2 and M phase cell. The traditional Chinese medicine composition is mainly used for treating non-small cell lung cancer and metastatic breast cancer in clinic.

The predominant form of administration currently used in the clinic is the intravenous route. The pharmacokinetics after intravenous administration is in a three-chamber model, the average half-life period of the terminal phase is 40 hours, the clearance rate of plasma is higher and is about 800mL/kg body weight/hour, the tissue intake rate is high and lasting, and the excretion is mainly performed through excrement due to the high biliary tract clearance rate. Plasma protein binding levels were as high as 50-80%. However, in the medication process, phlebitis occurs at the puncture site of 19.1% -40.5% of patients, which affects further medication, and has attracted attention of clinicians.

To overcome the disadvantages of intravenous administration, oral dosage forms containing vinorelbine have been studied. PCT patent application publication No. CN 1638745 a (published as 7/13/2005) discloses a liquid fill composition suitable as a dosage form for soft capsules comprising: vinorelbine or its pharmaceutically acceptable salt, ethanol, water, glycerol and polyethylene glycol. In the liquid fill composition, the presence of ethanol and polyethylene glycol as co-solvents plays an important role in the stability and solubility of vinorelbine and the stability of the capsule shell, but must simultaneously contain a suitable proportion of water and a certain weight ratio of water to alcohol, otherwise the soft capsule will exhibit a "dent" effect during storage. With this improvement, vinorelbine, the active ingredient, has improved solubility and stability in this composition, and has effective bioavailability after ingestion.

However, the prescription of the composition is complex, and unsatisfactory places which need further improvement exist, such as the stability of active ingredients, the negative promotion effect of auxiliary materials on adverse reactions after the medicine is taken, and the like.

Disclosure of Invention

The invention aims to solve the technical problem of providing a vinorelbine soft capsule liquid filling composition with a simple prescription.

Another technical problem to be solved by the present invention is to provide a vinorelbine soft capsule liquid filling composition with further improved prescription stability.

The invention aims to solve another technical problem of providing a vinorelbine soft capsule liquid filling composition which does not further aggravate adverse reactions after the administration of the medicine due to auxiliary materials in a prescription.

The inventor researches the influence of each raw and auxiliary material component in the prescription of the medicament on the treatment effect of the preparation and the like, and discovers that: glycerol itself has an effect of moisturizing the intestine, and although glycerol is generally used as a common solvent filler for soft capsules, it is not intended to be avoided by those skilled in the art. However, the inventors have surprisingly found that: the glycerol is used as an auxiliary material and added into the vinorelbine soft capsule, which can aggravate diarrhea of tumor patients, so the vinorelbine soft capsule contains the potential risk of the auxiliary material glycerol tumor patients. Therefore, in the research process, on the premise of ensuring the solubility of the active ingredients of the preparation and the stability of the capsule, the selection and dosage proportion of other auxiliary materials are adjusted to achieve the purpose of reducing or avoiding the use of glycerin. In the process of adjusting the dosage ratio of each component, it is further found that when the water in the prescription is deleted, the stability of the preparation is more favorably improved. While water in the formulation was emphasized in CN 1638745 a on the importance of formulation stability, the present inventors found that the removal of glycerin and water from the formulation did not affect the stability of the soft capsule even though the water was removed from the formulation, and more unexpectedly, the stability of the liquid fill composition of the specific composition and ratio of the present invention was further improved by the removal of water. This result is unexpected to those skilled in the art. Therefore, the object of the present invention is to provide a vinorelbine soft capsule liquid filling composition, which comprises vinorelbine or its salt, ethanol and polyethylene glycol, and does not contain water and glycerin, so as to solve the above technical problems.

The prescription of the invention overcomes the diarrhea influence of the glycerol in the CN 1638745A preparation on tumor patients, simplifies the prescription and the process and obtains the preparation with better stability. In addition, because the prescription has simple components and the mutual influence between the auxiliary materials and the raw materials is less, the weight ratio of the ethanol to the polyethylene glycol can be adjusted according to the requirement of maintaining the solubility of the medicine in the capsule content and the stability of the preparation. Preferably, the weight ratio of ethanol to polyethylene glycol in the soft capsule liquid fill composition of the present invention is from 1: 20 to 1: 10, preferably from 1: 18 to 1: 11, more preferably from 1: 16 to 1: 12, more preferably from 1: 15 to 1: 13, and most preferably 1: 14.

The vinorelbine soft capsule provided by the invention is calculated by taking the total weight of the vinorelbine or the salt thereof, the ethanol and the polyethylene glycol contained in the liquid filling composition as 100 percent, and has better indexes when the vinorelbine or the salt thereof is 1 to 10 percent, the ethanol is 2 to 30 percent and the polyethylene glycol is 60 to 95 percent; preferably 3-7% of vinorelbine or vinorelbine salt, 3-10% of ethanol and 85-95% of polyethylene glycol; most preferably, vinorelbine or its salt is about 4%, ethanol is about 6%, and polyethylene glycol is about 90%.

Preferably, in the composition, vinorelbine is its tartrate salt, and the amount of vinorelbine tartrate is determined according to the dissolved amount of vinorelbine tartrate in a mixture of ethanol and polyethylene glycol and the unit dosage, and the content of vinorelbine or its salt in the vinorelbine as its original drug is 5-100 mg/capsule, preferably 10-80 mg/capsule, more preferably 20-70 mg/capsule, even more preferably 25-50 mg/capsule, and most preferably 20-30 mg/capsule. When the selected vinorelbine or its salt is vinorelbine tartrate, the corresponding content of vinorelbine tartrate is 5-120 mg/capsule, preferably 10-90 mg/capsule, further preferably 20-80 mg/capsule, more preferably 25-60 mg/capsule, and most preferably 27.7-41.5 mg/capsule.

The vinorelbine or salt thereof is present in an amount of 2% to 27%, preferably 2% to 15%, more preferably 3.5% to 4.5%, most preferably about 4% by weight of the total liquid filling composition. The polyethylene glycol has an average molecular weight of 200-.

The invention also provides a method for preparing the vinorelbine soft capsule. When the soft capsule is prepared, all the components in the composition are mixed, dissolved and encapsulated in a soft capsule material according to the dissolution characteristics. Generally, ethanol and polyethylene glycol are mixed, after mixing, vinorelbine or its salt (preferably vinorelbine tartrate) is added, stirred to dissolve the vinorelbine or its salt into clear liquid, and then soft capsule encapsulation is carried out. Other components, such as antioxidant and the like, can be added in the preparation process according to the needs of the process. The addition of these components may be selected depending on the solubility and may be carried out in the respective dissolution steps. Specifically, when the soft capsule of the present invention is prepared, the prescribed amount of ethanol and polyethylene glycol are taken in a clean container, the prescribed amount of vinorelbine tartrate raw material is added while stirring, and the mixture is stirred to dissolve the vinorelbine tartrate raw material to form a clear liquid filling composition. The fill composition is then encapsulated in a soft capsule material on a softgel machine, pressed into pellets, and dried.

On the other hand, the invention provides the application of the vinorelbine soft capsule in preparing the anti-tumor drugs, in particular the application in the drugs for treating non-small cell lung cancer or metastatic breast cancer.

Detailed Description

The present invention will be described in detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit of the present invention.

Example 1 prescription screening of Soft capsules

Preparation: taking the prescription amount of each auxiliary material according to the following prescription A-C, adding the prescription amount of the vinorelbine tartrate raw material into a clean container while stirring, and stirring to dissolve the raw material to form a clear liquid. Then encapsulating the liquid in soft capsule material composed of gelatin on a soft capsule machine, pressing into pill, and drying.

TABLE 1 formulation composition of vinorelbine Soft capsules

See table 2 for the results of stability studies for formulations a-C.

TABLE 2 dissolution data of vinorelbine soft capsules and related substances

	A	B	C
				When the preparation is completed	Vinorelbine was completely dissolved and slightly viscous.	Vinorelbine was completely dissolved and slightly viscous.	Vinorelbine was completely dissolved and slightly viscous.
Sealing and standing at 25 deg.C for 5 days	The character is unchanged, and the related substances are increased by about 1.6 percent compared with the initial substances	The character is unchanged, and the related substances are increased by about 0.05 percent compared with the initial substances	The character is unchanged, and the related substances are increased by about 1.2 percent compared with the initial substances
				Sealing and standing at low temperature (2-8 deg.C) for 5 days	n.p.	The character is unchanged, and the related substances are increased by about 0.04% compared with the original substances	The character is unchanged, and the related substances are increased by about 0.6 percent compared with the initial substances

Table 2 shows that: after the aqueous preparations A and C are placed at room temperature or low temperature for 5 days, the degradation of the vinorelbine to generate related substances can be increased by about 0.6-1.6 percent, and the content of the related substances after the degradation of the vinorelbine in the aqueous preparation B is not obviously changed. Therefore, the elimination of water from the prescription not only improves the stability of the prescription, but also does not change the appearance of the soft capsule obviously.

Examining the stability of formulation A, B, C to see: after glycerin is removed from the preparation, when the amount of water is zero, the formula B has a good stabilizing effect. Therefore, the prescription is determined to be free of water and glycerin, mainly using ethanol and polyethylene glycol as solvents.

Example 2 soft capsule liquid fill composition recipe (1000 capsules):

vinorelbine tartrate 27.7g

Ethanol 70g

Polyethylene glycol 400707.3 g

Example 3 soft capsule liquid fill composition recipe (1000 capsules):

vinorelbine tartrate 41.5g

65g of ethanol

Polyethylene glycol 400707.5 g

Example 4 soft capsule liquid fill composition recipe (1000 capsules):

vinorelbine tartrate 27.7g

42.3g of ethanol

Polyethylene glycol 400620 g

Test example 1 examination of stability of Soft Capsule preparation

The appearance, content color, content and related substances of the soft capsule during the placement process were examined according to the adverse changes that the soft capsule may produce.

The test method comprises the following steps: the hard polyvinyl chloride (PVC) sheet for medicine and the aluminum foil for medicine packaging are used as packaging materials, the packaging materials are sealed and packaged in a heat seal mode, the hard PVC sheet is placed for 12 months at a low temperature (2-8 ℃), and the measurement results are shown in table 3.

And (4) investigating items: 1) appearance of the soft capsule: visual inspection is adopted; 2) color of the contents: the color change state is judged by diluting the concentration of vinorelbine in each ml with water to be 10mg and measuring the absorbance at the wavelength of 420nm by using ultraviolet absorption; 3) the content measurement and related substance detection are performed by High Performance Liquid Chromatography (HPLC).

TABLE 32-8 deg.C Low temperature Retention test results

As seen from table 3: the color indexes of the contents are not obviously changed when the contents are examined for 3 months, 6 months, 9 months and 12 months at the temperature of 2-8 ℃: compared with the prior art, the content measurement indexes have no obvious difference, and related substances show extremely low impurity percentage values in the measurement time, which shows that the vinorelbine soft capsule is relatively stable, the appearance of the soft capsule is not obviously influenced by the prescription after water and glycerin are removed, and the stability of the prescription is maintained.

The vinorelbine tartrate soft capsule obtained by the improvement of the inventor not only solves the problem of phlebitis in intravenous route administration, but also is convenient for patients to use; the prescription of the soft capsule filling composition is simplified, the industrial manufacture is facilitated, the stability of the preparation is further improved, the negative effect of auxiliary materials on the adverse effect of the medicine is reduced, and the soft capsule filling composition has better social benefit and economic benefit.

Claims

1. A vinorelbine soft capsule is characterized in that a soft capsule liquid filling composition contains vinorelbine or a salt thereof, ethanol and polyethylene glycol, and does not contain water and glycerol, wherein the weight ratio of the ethanol to the polyethylene glycol is 1: 20-1: 10, and the total weight of the vinorelbine or the salt thereof, the ethanol and the polyethylene glycol contained in the liquid filling composition is 100%, the content of the vinorelbine or the salt thereof is 1-10%, the content of the ethanol is 2-30%, and the content of the polyethylene glycol is 60-95%.

2. The vinorelbine soft capsule according to claim 1, wherein the vinorelbine or the salt thereof is vinorelbine tartrate.

3. The vinorelbine soft capsule according to claim 1 or 2, wherein the polyethylene glycol has an average molecular weight of 200-600 daltons.

4. The vinorelbine soft capsule of claim 3, wherein the polyethylene glycol has an average molecular weight of 300 and 400 daltons.

5. The vinorelbine soft capsule of claim 4, wherein the polyethylene glycol has an average molecular weight of 400 daltons.

6. The vinorelbine soft capsule according to claim 1 or 2, wherein the weight ratio of ethanol to polyethylene glycol in the liquid fill composition is from 1: 18 to 1: 11.

7. The vinorelbine soft capsule of claim 6, wherein the weight ratio of ethanol to polyethylene glycol in the liquid fill composition is from 1: 16 to 1: 12.

8. The vinorelbine soft capsule of claim 7, wherein the weight ratio of ethanol to polyethylene glycol in the liquid fill composition is from 1: 15 to 1: 13.

9. The vinorelbine soft capsule of claim 8, wherein the weight ratio of ethanol to polyethylene glycol in the liquid fill composition is 1: 14.

10. The vinorelbine soft capsule according to claim 1 or 2, wherein the vinorelbine or its salt, ethanol 3-10%, and polyethylene glycol 85-95% by total weight of the vinorelbine or its salt, ethanol, and polyethylene glycol contained in the liquid filling composition is 100%.

11. The vinorelbine soft capsule of claim 10, wherein the vinorelbine or salt thereof, ethanol, and polyethylene glycol comprise 4%, 6%, and 90% by weight of the total weight of the vinorelbine or salt thereof, ethanol, and polyethylene glycol present in the liquid fill composition, calculated as 100%.

12. The vinorelbine soft capsule according to claim 2, wherein the vinorelbine tartrate is present in an amount of 2 to 15% by weight of the total liquid fill composition.

13. The vinorelbine soft capsule of claim 12, wherein the vinorelbine tartrate is present in an amount of 3.5% to 4.5% by weight of the total liquid fill composition.

14. The vinorelbine soft capsule of claim 13, wherein the vinorelbine tartrate is present in an amount of 4% by weight of the total liquid fill composition.

15. The vinorelbine soft capsule according to claim 1, wherein the vinorelbine or its salt is present in an amount of 5-100mg per capsule, based on the vinorelbine as its native drug.

16. The vinorelbine soft capsule of claim 15, wherein the vinorelbine or the salt thereof is present in an amount of 10-80mg per capsule, based on the vinorelbine as its native drug.

17. The vinorelbine soft capsule of claim 16, wherein the vinorelbine or the salt thereof is present in an amount of 20-70mg per capsule, based on the vinorelbine as its native drug.

18. The vinorelbine soft capsule of claim 17, wherein the vinorelbine or salt thereof is present in an amount of 25-50mg per capsule based on the vinorelbine as its native drug.

19. The vinorelbine soft capsule of claim 17, wherein the vinorelbine or salt thereof is present in an amount of 20mg to 30mg per capsule based on the vinorelbine as its native drug.

20. The vinorelbine soft capsule of claim 1, wherein the vinorelbine or salt thereof is vinorelbine tartrate, the vinorelbine tartrate being present in an amount of 5 to 120mg per capsule.

21. The vinorelbine soft capsule of claim 20, wherein the vinorelbine tartrate is present in an amount of 10 to 90mg per capsule.

22. The vinorelbine soft capsule of claim 21, wherein the vinorelbine tartrate is present in an amount of 20 to 80mg per capsule.

23. The vinorelbine soft capsule of claim 22, wherein the vinorelbine tartrate is present in an amount of 25 to 60mg per capsule.

24. The vinorelbine soft capsule of claim 23, wherein the vinorelbine tartrate is present in an amount of from 27.7mg to 41.5mg per capsule.

25. The vinorelbine soft capsule according to claim 2, wherein the composition of the liquid fill composition is, per 1000 soft capsules: 27.7g of vinorelbine tartrate, 70g of ethanol and 707.3g of polyethylene glycol 400; or 41.5g of vinorelbine tartrate, 65g of ethanol and 707.5g of polyethylene glycol 400; or 27.7g of vinorelbine tartrate, 42.3g of ethanol and 620g of polyethylene glycol 400.

26. The process for preparing vinorelbine soft capsules according to any one of claims 1 to 25, wherein the components of the liquid fill composition of the soft capsule are mixed and dissolved and then encapsulated in the soft capsule material.

27. The process of claim 26, wherein the ethanol and polyethylene glycol are mixed, the mixture is added with vinorelbine or a salt thereof, and the mixture is stirred to dissolve the vinorelbine or the salt thereof into a clear liquid, and the soft capsule is encapsulated.

28. The method of claim 27, wherein the vinorelbine or salt thereof is vinorelbine tartrate.

29. Use of the vinorelbine soft capsule according to any one of claims 1 to 25 for the preparation of an antitumor drug.

30. The use of the vinorelbine soft capsule of claim 29 for preparing an antitumor drug, wherein the antitumor drug is a drug for treating non-small cell lung cancer or metastatic breast cancer.