CN115300486A - Meloxicam orally dissolving film agent and preparation method and application thereof - Google Patents

Abstract

The invention discloses a meloxicam orally dissolving film agent, a preparation method and application thereof. The composite material comprises the following components in percentage by mass: 40 to 55 percent of meloxicam; 30-50% of macromolecular film-forming agent; 1 to 15 percent of defoaming agent; 1 to 20 percent of plasticizer; 1 to 20 percent of flavoring agent; the macromolecular film forming agent is a mixture of hydroxypropyl fiber and polyoxyethylene. The invention selects hydroxypropyl fiber and polyethylene oxide as macromolecule film forming agent to be used for forming the film of meloxicam; can greatly improve the drug loading rate of the orally dissolving film agent, promote the dissolution rate of the meloxicam and avoid bubbles and particles on the surface of the orally dissolving film agent.

Description

Meloxicam orally dissolving film agent and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to a meloxicam orally dissolving film agent and a preparation method and application thereof.

Background

The oral dissolving film agent is a film preparation prepared by processing a medicament and a proper film forming material and is used for oral administration or mucous membrane. The oral instant film agent has the following advantages: 1) Small volume, light weight, convenient carrying, storage and transportation, 2) accurate dosage, simple preparation process, lower cost and stable property: 3) Can be taken without water, can be dissolved by being placed on the tongue tip, and can be taken at any time and any place: 4) After being taken, the medicine can be quickly dissolved and released, and part of the medicine can directly enter a blood system through mucous membrane, so that the first-pass effect is avoided: 5) Has good compliance, is especially suitable for children, the elderly and dysphagia patients with emesis symptoms, and can be dissolved immediately when placed into the mouth to prevent children from spitting.

Meloxicam is a nonsteroidal antipyretic analgesic, exerts analgesic and anti-inflammatory effects by inhibiting synthesis of prostaglandin, has light side effects, and can be used for treating osteoarthritis and rheumatoid arthritis. Currently marketed dosage forms containing meloxicam include tablets, capsules, suspensions, injections, and the like. However, for a 7.5mg film agent, if the content of the meloxicam raw material drug is higher than 40%, particles are easy to appear on the surface when the orally dissolving film agent is prepared, the appearance is not easy to accept, and the content uniformity of the meloxicam main drug is poor under the condition, so that the clinical effectiveness and safety are influenced; if the content of the meloxicam raw material drug is lower than 40%, the weight of a 7.5mg film agent single piece exceeds 50mg, the film thickness is large, rapid dissolution in the oral cavity is not easy, and the patient compliance is poor.

Therefore, there is a need to develop a meloxicam oral film formulation, which has high drug effect loading and does not have particles on the surface of the film formulation.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. To this end, the invention provides in a first aspect a meloxicam orally disintegrating film formulation.

The second aspect of the invention also provides a preparation method of the meloxicam oral dissolving film agent.

The third aspect of the invention also provides an application of the meloxicam oral dissolving film agent.

The oral dissolving film agent according to the embodiment of the first aspect of the invention comprises the following components in percentage by mass:

the macromolecular film forming agent is a mixture of hydroxypropyl fiber and polyoxyethylene.

The meloxicam oral dissolving film agent provided by the embodiment of the invention has at least the following beneficial effects:

the invention selects hydroxypropyl fiber and polyethylene oxide as macromolecule film forming agent to form meloxicam film; the drug-loading rate of the oral dissolving film agent can be greatly improved, because the polyoxyethylene has stronger thickening and forming functions, and the hydroxypropyl cellulose has stronger adsorption function, and the functions of the polyoxyethylene and the hydroxypropyl cellulose are complementary and have good compatibility; on the other hand, the hydroxypropyl fiber and the polyethylene oxide are selected as the high-molecular film forming agent, so that the dissolution rate of the meloxicam can be promoted.

According to some embodiments of the invention, the mass ratio of the hydroxypropyl fibers and the polyethylene oxide is 1: (4-10). Thereby, the dissolution rate of meloxicam is further improved.

According to some embodiments of the invention, the meloxicam has a D50 particle size of 5 μm to 50 μm. Too large a particle size results in a film which is too coarse and too fine a particle size changes the pharmacokinetic profile of the material.

The defoaming agent is at least one selected from simethicone, glycerol, GPE10, GPE20, GPE50, tween 20, tween 60 or Tween 80.

According to some embodiments of the invention, the plasticizer comprises at least one of glycerol, propylene glycol, PEG, sorbic acid, citric acid, sorbitol, or triethyl citrate.

According to some embodiments of the invention, the flavoring agent comprises at least one of glucose, sucralose, cyclamate, saccharin, aspartame, peppermint flavor, orange flavor, or strawberry flavor.

According to some embodiments of the invention, the meloxicam orally disintegrating film further comprises at least one of a coloring agent, an opacifier, or a stabilizer.

According to some embodiments of the present invention, the colorant, without particular limitation, may be a colorant pharmaceutical adjuvant conventional in the art, such as a blue pigment and the like.

According to some embodiments of the invention, the stabilizing agent comprises at least one of edetic acid, tea polyphenols, tocopherols or butylated hydroxyanisole.

According to some embodiments of the invention, the opacifier includes at least one of titanium dioxide, silicon dioxide, or zinc oxide.

In a second aspect, the present invention provides a method for preparing a meloxicam orally disintegrating film, comprising the following steps:

s1, stirring meloxicam, a flavoring agent and a solvent to obtain a first mixture;

s2, mixing, stirring and defoaming the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer to obtain a second mixture;

s3, coating the second mixture on a backing material, drying, stripping and cutting to obtain the meloxicam oral dissolving film agent;

the solvent is a mixed solution of ethanol and water.

The preparation method of the oral dissolving film agent provided by the embodiment of the invention at least has the following beneficial effects:

the inventor finds that the meloxicam raw material medicine belongs to an insoluble medicine, when the content of the raw material medicine is higher than 40%, the raw material medicine is not easy to disperse in the process of preparing a medicine solution, and the medicine solution contains more bubbles, and even if a defoaming agent is added, the bubbles still exist; in the drying process, the raw materials are migrated and aggregated along with the reduction of moisture to form an agglomeration phenomenon, and the prepared film agent has bubble holes and obvious particles on the surface and is not easy to accept in appearance; in addition, the content uniformity of the meloxicam main drug is poor under the condition, and the clinical effectiveness and safety are influenced.

The research of the invention finds that if ethanol and water are selected as solvents, the particles on the surface of the film agent caused by agglomeration in the drying process can be avoided; and can also assist in reducing the problem of bubbles that occur during the manufacturing process. So that the prepared meloxicam oral dissolving film agent has better uniformity and effectiveness.

According to some embodiments of the invention, the mass ratio of ethanol to water is 1: (1-2).

According to some embodiments of the invention, the backing material comprises at least one of PET, PP.

According to some embodiments of the invention, in step S1, the stirring speed is 50 to 100r/min; the stirring time is 20-40 min.

The third aspect of the invention provides the application of the meloxicam oral film dissolving agent in the preparation of osteoarthritis or rheumatoid arthritis drugs.

Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Drawings

The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:

fig. 1 is an appearance diagram of the meloxicam orally dissolving film prepared in comparative example 3.

Detailed Description

The following are specific examples of the present invention, and the technical solutions of the present invention will be further described with reference to the examples, but the present invention is not limited to the examples.

The reagents, methods and equipment adopted by the invention are conventional in the technical field if no special description is given.

The raw materials used in the examples and comparative examples are as follows:

the meloxicam raw material medicine comprises: jiangsu Feima pharmaceutical Co., ltd;

meloxicam tablets: is sold on the market;

high-molecular film forming agent: carrekang pharmaceutical co;

defoaming agent: mannitol; french rogowski;

plasticizer: glycerol; new green prescription pharmaceutical limited, hunan;

flavoring agent: sucralose; jiangxi alpha high-tech company, inc.

Example 1

Example 1 provides a meloxicam orally dissolving film formulation, the component content is shown in table 1, the preparation method is as follows:

s1, stirring meloxicam, a flavoring agent, ethanol and water to obtain a first mixture;

s2, mixing the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer, stirring and defoaming in vacuum for 2 hours to obtain a second mixture;

s3, coating the second mixture on a backing material, drying at 50 ℃, stripping and cutting to obtain the meloxicam orally dissolving film agent;

the mass ratio of the ethanol to the water is 1.5.

Example 2

Embodiment 2 provides a meloxicam orally dissolving film formulation, the component content is shown in table 1, the preparation method is as follows:

s1, stirring meloxicam, a flavoring agent, ethanol and water to obtain a first mixture;

s2, mixing, stirring and vacuum defoaming the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer for 2 hours to obtain a second mixture;

s3, coating the second mixture on a backing material, drying at 50 ℃, stripping and cutting to obtain the meloxicam orally dissolving film agent;

the mass ratio of the ethanol to the water is 1.5.

Example 3

Example 3 provides a meloxicam orally disintegrating film formulation, the component content is shown in table 1, the preparation method is as follows:

s1, stirring meloxicam, a flavoring agent, ethanol and water to obtain a first mixture;

s2, mixing the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer, stirring and defoaming in vacuum for 2 hours to obtain a second mixture;

s3, coating the second mixture on a backing material, drying at 50 ℃, stripping and cutting to obtain the meloxicam orally dissolving film agent;

the mass ratio of the ethanol to the water is 1.5.

Example 4

Example 4 provides a meloxicam orally disintegrating film formulation, the contents of the components are shown in table 1, and the preparation method is as follows:

s1, stirring meloxicam, a flavoring agent, ethanol and water to obtain a first mixture;

s2, mixing the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer, stirring and defoaming in vacuum for 2 hours to obtain a second mixture;

s3, coating the second mixture on a backing material, drying at 50 ℃, stripping and cutting to obtain the meloxicam orally dissolving film agent;

the mass ratio of the ethanol to the water is 1.5.

Example 5

Example 5 provides a meloxicam orally disintegrating film formulation, the component content is shown in table 1, the preparation method is as follows:

s1, stirring meloxicam, a flavoring agent, ethanol and water to obtain a first mixture;

s2, mixing, stirring and vacuum defoaming the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer for 2 hours to obtain a second mixture;

s3, coating the second mixture on a backing material, drying at 50 ℃, stripping and cutting to obtain the meloxicam orally dissolving film agent; the mass ratio of the ethanol to the water is 1.5.

TABLE 1 component contents of examples 1 to 5

Examples 6 to 9

Examples 6-9 provide a series of meloxicam orally disintegrating films having the same composition and preparation method as example 3, except for the volume of the solvent, as shown in Table 2.

TABLE 2 examples 6 to 9

Comparative example 1

Comparative example 1 provides a meloxicam orally disintegrating film formulation, which has the same component content and preparation method as example 1, except that the polymeric film forming agent is 56% hydroxypropyl fiber, and the meloxicam dosage is 27%.

Comparative example 2

Comparative example 2 provides a meloxicam orally disintegrating film formulation, which has the same contents of components and preparation method as example 1, except that the polymeric film forming agent is polyoxyethylene 49% and the meloxicam amount is 34%.

Comparative example 3

Comparative example 3 provides a series of meloxicam orally dissolving films having the same contents of ingredients and preparation method as example 3, except that the solvent is water.

FIG. 1 is the appearance of the meloxicam orally dissolving film formulation of comparative example 3, which has surface pores, distinct particles and wrinkles, and the appearance is unsatisfactory.

Performance test

Dissolution testing: 6 tablets of this product (examples 1 to 9 and comparative examples 1 to 3) and 6 commercially available meloxicam tablets (7.5 mg standard) were taken and examined for the dissolution curves of orally disintegrating tablets and commercially available tablets according to the general rule of Chinese pharmacopoeia (2020 edition) by reference to the first method of the general rule 0931. The specific method comprises the following steps: the paddle method is carried out for 50 turns, the dissolution medium is 100mL of degassed purified water with the pH value of 1.0, and the dissolution sample is detected by adopting a high performance liquid chromatography, wherein the detection wavelength is 320nm. The results are shown in Table 3.

TABLE 3 dissolution data for examples 1-9 and comparative examples 1-3

5min

10min

15min

30min

60min

90min

Example 1

53％

69％

79％

85％

90％

97％

Example 2

75％

86％

91％

96％

99％

100％

Example 3

79％

89％

96％

99％

99％

99％

Example 4

80％

91％

100％

1005

100％

100％

Example 5

70％

78％

85％

95％

95％

100％

Example 6

79％

80％

92％

100％

100％

100％

Example 7

65％

80％

90％

95％

98％

100％

Example 8

61％

66％

79％

90％

95％

100％

Example 9

54％

61％

72％

89％

96％

99％

Comparative example 1

43％

51％

62％

70％

86％

91％

Comparative example 2

39％

48％

71％

79％

90％

95％

Comparative example 3

48％

59％

68％

81％

90％

96％

From the data analysis of table 3, in examples 1 to 5; with the decrease of the dosage of the high molecular material hydroxypropyl methylcellulose, the dissolution rate of the film agent is accelerated, but when the dosage of the hydroxypropyl methylcellulose is reduced to a certain value, the dissolution rate is slowed, which indicates that the mass ratio of the hydroxypropyl cellulose to the polyethylene oxide is 1: (4-10), which is more advantageous for elution of the raw material.

In examples 3 and 6 to 9, the decrease in film dissolution was caused with the increase in the amount of water, which is probably due to the uneven content caused by the easy delivery and migration of raw materials during the preparation of film using water as a solvent, thereby causing the decrease in dissolution.

In comparative examples 1 to 3, the dissolution of each film agent is less, which indicates that the mixed polymer material and the mixed solvent have a certain beneficial effect on accelerating the dissolution of the film agent.

And (3) testing uniformity: taking 1 tablet (examples 1-9 and comparative examples 1-3) of the product, placing the tablet in a 100mL measuring flask, adding a mobile phase for dissolving, diluting to a scale, shaking uniformly, standing, taking supernatant for filtering, taking subsequent filtrate as a test solution, preparing ten parts in parallel, measuring the content by using an HPLC method, and measuring the content uniformity (A +2.2S is less than or equal to 20.0) according to four parts of 2020 version of Chinese pharmacopoeia. The results are shown in Table 4.

TABLE 4 uniformity data for examples 1-9 and comparative examples 1-3

From the data analysis of table 3, the ethanol dosage in examples 6 to 9 and comparative example 3 is reduced in sequence, and as a result, the content uniformity of the prepared sample is found to be deteriorated in sequence, and the reason for the analysis is that the surface tension of water is large, when the water content is too much, bubbles are easily generated and the viscosity of the aqueous solution is larger than that of the ethanol solution, so that the bubbles are not easily removed, when the film is dried, the bubbles are broken, so that the surface of the film is uneven and the content is not uniform, if the ethanol content is too high, an explosion-proof device needs to be additionally arranged in the industrial production, so that the safety is slightly poor, and the economic cost is correspondingly improved.

In vivo pharmacokinetic testing: comparison of the pharmacokinetics of meloxicam orally dissolving films (example 3) with meloxicam tablets (shanghai berg haggarhan): the test was conducted using a three-cycle crossover test design, wherein subjects were administered the oral cavity spray of example 3 (7.5 mg pre-meal), with 5 days of wash cycle, followed by 5 days of elution and then a commercial tablet (7.5 mg pre-meal). Plasma samples were collected at different time points after dosing, pharmacokinetic parameters were calculated by DAS software, and the results are shown in table 5.

TABLE 5 pharmacokinetic data for example 3 and commercially available tablets

The result shows that the self-made oral dissolving film preparation Tmax is faster than the tablet sold in the market, which indicates that the oral dissolving film preparation can take effect more quickly when being taken. And the Cmax and AUC of the orally dissolving film agent are similar to those of the commercially available preparation, which indicates that the orally dissolving film agent does not change the safety of the medicine. In conclusion, the self-made orally dissolving film agent can replace the preparation sold in the market for use, does not influence the safety of the preparation, and has quicker effect.

The present invention is not limited to the above-described embodiments, and various changes can be made without departing from the spirit and scope of the present invention within the knowledge of those skilled in the art.

Claims (10)

1. The meloxicam oral dissolving film agent is characterized by comprising the following components in percentage by mass:

the macromolecular film forming agent is a mixture of hydroxypropyl fiber and polyoxyethylene.

2. The meloxicam orally disintegrating film formulation according to claim 1, wherein the mass ratio of the hydroxypropyl fiber to the polyethylene oxide is 1: (4-10).

3. The meloxicam orally disintegrating film formulation according to claim 1, wherein the particle size D50 of meloxicam ranges from 5 μm to 50 μm.

4. The meloxicam orally disintegrating film formulation according to claim 1, wherein the antifoaming agent is at least one selected from the group consisting of mannitol, dimethicone, glycerol, GPE10, GPE20, GPE50, tween 20, tween 60 and tween 80.

5. The meloxicam orally dissolving film formulation according to claim 1, wherein the plasticizer comprises at least one of glycerin, propylene glycol, PEG, sorbic acid, citric acid, sorbitol or triethyl citrate.

6. The meloxicam orally disintegrating film formulation according to claim 1, wherein the flavoring agent comprises at least one of dextrose, sucralose, sodium cyclamate, saccharin, aspartame, peppermint flavor, orange flavor, or strawberry flavor.

7. The meloxicam orally dissolving film formulation according to claim 1, wherein said meloxicam orally dissolving film formulation further comprises at least one of a colorant, a sunscreen, or a stabilizer.

8. The method for preparing a meloxicam orally dissolving film dosage according to any of claims 1 to 7, comprising the following steps:

s1, stirring meloxicam, a flavoring agent and a solvent to obtain a first mixture;

s2, mixing, stirring and defoaming the first mixture, the high-molecular film-forming agent, the defoaming agent and the plasticizer to obtain a second mixture;

s3, coating the second mixture on a backing material, drying, stripping and cutting to obtain the meloxicam oral dissolving film agent;

the solvent is a mixed solution of ethanol and water.

9. The method for preparing a meloxicam orally dissolving film formulation according to claim 8, wherein the mass ratio of ethanol to water is 1: (1-2).

10. Use of a meloxicam oral film dosage form according to any one of claims 1 to 7 for the preparation of a medicament for osteoarthritis or rheumatoid arthritis.

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