CN114515278B

CN114515278B - Mecobalamin oral sustained-release film and preparation method thereof

Info

Publication number: CN114515278B
Application number: CN202210226940.7A
Authority: CN
Inventors: 李佳凯; 张蕾; 蔡正军; 杨卓理; 韩雅慧; 易斌
Original assignee: Beijing Silian Pharmaceutical Industry Co ltd
Current assignee: Beijing Silian Pharmaceutical Industry Co ltd
Priority date: 2022-03-08
Filing date: 2022-03-08
Publication date: 2023-11-14
Anticipated expiration: 2042-03-08
Also published as: CN114515278A

Abstract

The invention relates to a mecobalamin oral slow-release film and a preparation method thereof. The mecobalamin oral slow-release film comprises the following raw material components in parts by weight: 2-8 parts of mecobalamin, 15-40 parts of film forming agent, 10-40 parts of adhesive and 10-30 parts of plasticizer; wherein the adhesive is hypromellose and/or carboxymethylcellulose sodium; the plasticizer is triethyl citrate. The mecobalamin oral slow-release film agent can be slowly dissolved in the oral cavity, can continuously release and absorb the medicine, and has good viscosity and good medicine content stability in the oral cavity.

Description

Mecobalamin oral sustained-release film and preparation method thereof

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a mecobalamin oral slow-release film and a preparation method thereof.

Background

Mecobalamin is an endogenous coenzyme B12 that is capable of participating in the one-carbon unit cycle and plays an important role in the transmethylation of methionine from homocysteine. Animal experiments show that mecobalamin is easier to enter neuron cells and participate in synthesis of brain cells and spinal cord neuron thymidine, so that utilization of folic acid and nucleic acid metabolism are promoted, and the effect of promoting synthesis of nucleic acid and protein is stronger than that of mecobalamin.

Mecobalamin has many effects in the human body and also plays a different role for different people. For example, in the patients with peripheral injury, the muscles subjected to the nerve are subjected to atrophy due to no nutrition, gastrocnemius is subjected to nerve loss, muscle atrophy and reduced wet quality index, and mecobalamin can delay the muscle atrophy subjected to the nerve loss, and meanwhile, mecobalamin is used as an endogenous coenzyme type B12 and is easily transferred to the organelles of nerve cells, so that the mecobalamin has the effects of promoting the metabolism of nucleic acid, protein and fat in nerves, accelerating the repair of damaged nerve tissues and improving the transmission and metabolic disorder of the nerve tissues. In other groups, such as megaloblastic anemia patients, megaloblastic anemia is a clinical common nutritional anemia disease, the pathogenesis of megaloblastic anemia is mainly related to ineffective erythrocytes caused by DNA synthesis disorder of hematopoietic cells due to folic acid or vitamin B12 deficiency in vivo, and mecobalamin can promote maturation and division of normal erythrocyte, increase production of erythrocytes and improve anemia state, and can be used for treating megaloblastic anemia caused by vitamin B12 deficiency. In addition, mecobalamin can be taken by patients with neural tube defects to help reduce homocysteine and prevent occurrence of the neural tube defects.

At present, most of the medicines for mecobalamin are oral preparations such as tablets, capsules and the like, the mecobalamin tablet marketed in Japan is 0.25mg and 0.5mg, the mecobalamin tablet marketed in China by the medical company of the guard (China) is 0.5mg in specification, the oral preparations need to be swallowed by drinking water, and the administration compliance of old people and children is poor. Meanwhile, mecobalamin is a high-dissolution low-permeability drug, can be rapidly dissolved in a human body, but cannot be completely absorbed in the body.

The absorption through the oral mucosa is an absorption mode through the diffusion effect in the oral cavity. The medicine can permeate into the micro-blood vessels through the oral mucosa and then be brought into the internal circulation, so that the damage of livers, gastrointestinal tracts and enzymes can be avoided, and the effect is enhanced. The oral mucosa administration can also avoid the first pass effect of liver, accelerate and/or prolong the effect of the medicine, improve the bioavailability, reduce the administration times and stop the administration at any time. The mucosa in the oral cavity is thin, the area is large, and the oral cavity is easier to penetrate by medicines than the skin. Submucosa has a large number of capillaries that merge into the internal carotid artery and pass through the heart without passing through the liver. Thus, it is a further route of systemic administration which is worth studying, following dermal administration.

Disclosure of Invention

Based on the above, the invention provides the mecobalamin oral slow-release film capable of being absorbed by oral mucosa, which can be slowly dissolved in the oral cavity, continuously released and absorbed by the drug, and has good viscosity in the oral cavity and good drug content stability.

The invention provides a mecobalamin oral slow-release film, which comprises the following raw material components in parts by weight:

wherein the adhesive is hypromellose and/or carboxymethylcellulose sodium;

the plasticizer is triethyl citrate.

In one embodiment, the film former is copovidone and/or polyvinyl alcohol.

In one embodiment, the film former is copovidone.

In one embodiment, the raw material component further comprises a flavoring and/or coloring agent.

In one embodiment, the flavoring agent is 1-10 parts by weight; and/or

The flavoring agent is selected from one or more of sodium cyclamate, sodium saccharin and aspartame.

In one embodiment, the colorant is present in an amount of 0.001 to 0.005 parts by weight; and/or

The colorant is carmine and/or ferric oxide.

In one embodiment, the mecobalamin oral slow-release film comprises the following raw material components in parts by weight:

in a second aspect of the present invention, a preparation method of the mecobalamin oral slow-release film is provided, comprising the following steps:

dissolving the mecobalamin in water to prepare a mecobalamin solution;

mixing the film forming agent with warm water at 50-60 ℃, mixing the obtained polymer gel with the adhesive and the plasticizer, and cooling the obtained mixture to room temperature to prepare glue solution;

mixing the mecobalamin solution and the glue solution to obtain a medicine-containing solution;

performing film forming treatment and drying on the drug-containing solution to prepare the mecobalamin oral slow-release film;

all the steps are carried out under red light conditions.

In one embodiment, the feed liquid ratio of the film forming agent to the warm water at 50-60 ℃ is 1g (5-20) mL.

In one embodiment, the film forming process includes the steps of:

vacuum degassing the medicine-containing solution, and then coating;

wherein the vacuum degree of vacuum degassing is more than or equal to 0.080MPa, the temperature of a front plate of a coating film is 40-45 ℃, the temperature of a rear plate is 45-50 ℃, and the rotating speed is 250-300 r/min.

The mecobalamin oral slow-release film is prepared by reasonably matching the raw material components, particularly adopting a proper adhesive and a plasticizer, has a slow-release effect, is slowly dissolved in an oral cavity, continuously releases and is absorbed by the drug, and meanwhile, has good viscosity and good drug content stability in the oral cavity.

In addition, the mecobalamin oral slow-release film can be absorbed through oral mucosa, so that the absorption part of mecobalamin is increased, the problem that oral mecobalamin cannot be completely absorbed is effectively solved, the mecobalamin can be continuously released in the oral cavity for a long time, the blood concentration is maintained for a long time, the bioavailability is high, and side effects caused by too fast absorption of oral administration are avoided. Meanwhile, the tea has the advantages of no need of drinking water, convenient administration, good taste and good compliance for old people, children and patients with dysphagia in bed.

Detailed Description

The mecobalamin oral slow-release film and the preparation method thereof are further described in detail below with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

The term "and/or," "and/or," as used herein, includes any one of two or more of the listed items in relation to each other, as well as any and all combinations of the listed items in relation to each other, including any two of the listed items in relation to each other, any more of the listed items in relation to each other, or all combinations of the listed items in relation to each other.

Herein, "one or more" refers to any one, any two, or any two or more of the listed items.

In the present invention, "first aspect", "second aspect", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity of the indicated technical features. Moreover, "first," "second," etc. are for non-exhaustive list description purposes only, and it should be understood that no closed limitation on the number is made.

In the invention, the technical characteristics described in an open mode comprise a closed technical scheme composed of the listed characteristics and also comprise an open technical scheme comprising the listed characteristics.

In the present invention, the numerical ranges are referred to as continuous, and include the minimum and maximum values of the ranges, and each value between the minimum and maximum values, unless otherwise specified. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.

The percentage content referred to in the present invention refers to mass percentage for both solid-liquid mixing and solid-solid mixing and volume percentage for liquid-liquid mixing unless otherwise specified.

The percentage concentrations referred to in the present invention refer to the final concentrations unless otherwise specified. The final concentration refers to the ratio of the additive component in the system after the component is added.

The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a treatment within a predetermined temperature range. The constant temperature process allows the temperature to fluctuate within the accuracy of the instrument control.

The room temperature in the present invention is generally 4℃to 30℃and preferably 20.+ -. 5 ℃.

The invention provides a mecobalamin oral slow-release film which comprises the following raw material components in parts by weight:

wherein the adhesive is hypromellose and/or carboxymethylcellulose sodium;

the plasticizer is triethyl citrate.

Further, the binder is hypromellose. Still further, the binder is hypromellose K100M.

Further, in the mecobalamin oral slow-release film:

the weight portion of the mecobalamin is 2-8 portions, and concretely, the weight portion of the mecobalamin comprises but is not limited to: 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts.

The weight portion of the film forming agent is 15-40 portions, and concretely, the weight portion of the film forming agent comprises but is not limited to: 15 parts, 18 parts, 20 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 30 parts, 33 parts, 35 parts, 37 parts, 40 parts.

The weight portion of the adhesive is 10-40 portions, specifically, the weight portion of the adhesive includes but is not limited to: 10 parts, 15 parts, 18 parts, 20 parts, 25 parts, 27 parts, 28 parts, 29 parts, 30 parts, 31 parts, 33 parts, 35 parts, 37 parts, 40 parts.

The plasticizer is 10-30 parts by weight, specifically, the binder comprises, but is not limited to: 10 parts, 15 parts, 18 parts, 20 parts, 22 parts, 24 parts, 26 parts, 28 parts, 30 parts.

In one example, the film former is copovidone and/or polyvinyl alcohol. Further, the film forming agent is copovidone S-630. By adopting a proper film forming agent, the mecobalamin oral slow-release film has better slow-release effect and more uniform drug content, optimizes the appearance and the taste of the mecobalamin oral slow-release film, and effectively improves the bending resistance. Meanwhile, the degassing effect in the preparation process is better, the degassing time is shorter, the film is not cracked during film coating, and the film forming performance is better.

In one example, the raw material component further includes a flavoring and/or coloring agent.

In one example, the weight portion of the flavoring agent is 1-10, specifically, the weight portion of the flavoring agent includes but is not limited to: 1 part, 4 parts, 7 parts, 8 parts, 9 parts, 10 parts.

In one example, the flavoring agent is selected from one or more of sodium cyclamate, sodium saccharin, and aspartame. Further, the flavoring agent is saccharin sodium. The mecobalamin oral slow-release film has good taste and sweet taste by adopting a proper taste correction agent, and is more favored by patients.

In one example, the colorant is 0.001 to 0.005 parts by weight, specifically, the colorant includes, but is not limited to: 0.001 part, 0.002 part, 0.003 part, 0.004 part, and 0.005 part.

In one example, the colorant is carmine and/or ferric oxide. Further, the colorant is carmine. The mecobalamin oral slow-release film is not affected by light and has stable quality due to the fact that the appropriate coloring agent can be used for effectively shading light.

By adopting reasonably compatible raw material components, the mecobalamin oral slow-release film agent can be comprehensively provided with: 1) Better slow release effect; 2) Better viscosity, and is not easy to fall off when being stuck to the oral mucosa; 3) The degassing effect is good, the degassing time is shorter, the film is not easy to crack during film coating, and the film forming performance is better; 4) The appearance is smooth, the taste is good, the toughness is good, the folding times are more, and the peeling is easy; 5) The medicine content is uniform and stable.

In one example, the mecobalamin oral slow-release film comprises the following raw material components in parts by weight:

the invention also provides a preparation method of the mecobalamin oral slow-release film, which comprises the following steps:

dissolving the mecobalamin in water to prepare a mecobalamin solution;

all the steps are carried out under the condition of red light.

In one example, the illuminance of red light is 1-5 lx.

In one example, the concentration of the mecobalamin solution is 0.02 to 0.05g/mL.

In one example, the feed liquid ratio of the film forming agent to the warm water at 50-60 ℃ is 1g (5-20) mL.

Specifically, the temperature of the warm water includes, but is not limited to: 50 ℃, 52 ℃, 55 ℃,60 ℃.

Specifically, the feed liquid ratio of the film forming agent to the warm water at 50-60 ℃ comprises, but is not limited to: 1g:5mL, 1g:6mL, 1g:7mL, 1g:10mL, 1g:13mL, 1g:15mL, 1g:18mL, 1g:20mL.

In one example, the film forming process includes the steps of:

the drug-containing solution was vacuum deaerated and then film-coated.

In one example, the vacuum degree of vacuum degassing is not less than 0.080MPa. Further, the vacuum degree of vacuum degassing is 0.080MPa to 0.090MPa. Specifically, the vacuum degree of vacuum degassing includes, but is not limited to: 0.080MPa and 0.085MPa 0.090MPa.

In one example, the coating is carried out in a coating machine, the temperature of the front plate is 40-45 ℃, the temperature of the rear plate is 45-50 ℃, and the rotating speed is 250-300 r/min. It will be appreciated that the drug-containing solution after vacuum degassing needs to be allowed to cool down statically before coating.

In one example, the thickness of the coating film is controlled to be 75 μm to 100 μm. Specifically, the thickness of the coating film includes, but is not limited to: 75 μm, 80 μm, 85 μm, 90 μm, 100 μm.

In one example, the water is purified water.

In one example, the mixing steps are all performed under stirring. It is to be understood that the method of stirring is not particularly limited.

It can be easily understood that the specification of the mecobalamin oral slow-release film preparation is not limited, and the mecobalamin oral slow-release film can be cut according to the needs. Examples are a specification of 2cm by 2cm or 2cm by 3cm.

The following are specific examples. Unless otherwise indicated, all the starting materials used in the examples were commercially available products.

Example 1

The embodiment provides a mecobalamin oral slow-release film, the raw material components of which are shown in table 1:

TABLE 1

The preparation method of the mecobalamin oral slow-release film (all carried out under the condition of red light, the illuminance is 4 lx):

1) The mecobalamin is dissolved in purified water to obtain mecobalamin solution with the concentration of 0.05g/mL for standby.

2) Adding film forming agent copovidone S-630 into warm water at 50 ℃ under stirring to obtain polymer gel; the dosage ratio of the film forming agent to the warm water is 1g:5mL. Continuously adding the adhesive hydroxypropyl methylcellulose K100M, the plasticizer triethyl citrate, the flavoring agent saccharin sodium and the coloring agent carmine into the copolymer vidone S-630 polymer gel under the stirring state, uniformly stirring, and cooling to room temperature.

3) Under the stirring state, adding mecobalamin solution, and stirring uniformly to obtain the drug-containing solution.

4) Carrying out vacuum degassing treatment on the liquid medicine, wherein the vacuum degree of the vacuum degassing treatment is 0.085MPa; standing still for cooling.

5) Coating, namely setting the temperature of a front plate of a coating machine to 40 ℃, setting the temperature of a rear plate to 45 ℃, and preparing a film (controlling the film thickness to be 85 mu m) at the rotating speed of 280 r/min; and (3) stripping the medicinal film from the film material after film formation to prepare the mecobalamin oral slow-release film.

6) Cut into 3cm by 2cm.

Example 2

The example provides a mecobalamin oral slow-release film, the raw material components of which are shown in table 2:

TABLE 2

The preparation method of the mecobalamin oral slow-release film (all carried out under the condition of red light, the illuminance is 5 lx):

1) The mecobalamin is dissolved in purified water to obtain mecobalamin solution with the concentration of 0.02g/mL for standby.

2) Adding film forming agent copovidone S-630 into warm water at 55 ℃ under stirring to obtain polymer gel; the dosage ratio of the film forming agent to the warm water is 1g:10mL. Continuously adding the adhesive hydroxypropyl methylcellulose K100M, the plasticizer triethyl citrate, the flavoring agent saccharin sodium and the coloring agent carmine into the copolymer vidone S-630 polymer gel under the stirring state, uniformly stirring, and cooling to room temperature.

5) Coating, namely setting the temperature of a front plate of a coating machine to be 42 ℃, setting the temperature of a rear plate to be 46 ℃, and preparing a film (controlling the film thickness to be 75 mu m) at the rotating speed of 280 r/min; and (3) stripping the medicinal film from the film material after film formation to prepare the mecobalamin oral slow-release film.

6) Cut into 3cm by 2cm.

Example 3

The example provides a mecobalamin oral slow-release film, the raw material components of which are shown in table 3:

TABLE 3 Table 3

The preparation method of the mecobalamin oral slow-release film (all carried out under the condition of red light, the illuminance is 3 lx):

1) Dissolving mecobalamin in purified water to obtain mecobalamin solution with the concentration of 0.03g/mL for later use.

2) Adding film forming agent copovidone S-630 into warm water at 60 ℃ under stirring to obtain polymer gel; the dosage ratio of the film forming agent to the warm water is 1g:15mL is continuously added with the adhesive hydroxypropyl methylcellulose K100M, the plasticizer triethyl citrate, the flavoring agent saccharin sodium and the coloring agent carmine into the copolymer vidone S-630 polymer gel under the stirring state, and the mixture is uniformly stirred and then cooled to the room temperature.

4) Carrying out vacuum degassing treatment on the liquid medicine, wherein the vacuum degree of the vacuum degassing treatment is 0.090MPa; standing still for cooling.

5) Coating, namely setting the temperature of a front plate of a coating machine to 45 ℃, setting the temperature of a rear plate to 50 ℃, and preparing a film (controlling the film thickness to be 100 mu m) at the rotating speed of 280 r/min; and (3) stripping the medicinal film from the film material after film formation to prepare the mecobalamin oral slow-release film.

6) Cut into 3cm by 2cm.

Example 4

The example provides a mecobalamin oral slow-release film, the raw material components of which are shown in table 4:

TABLE 4 Table 4

The preparation method of the mecobalamin oral slow-release film (all carried out under the condition of red light, the illuminance is 1 lx):

1) Dissolving mecobalamin in purified water to obtain mecobalamin solution with the concentration of 0.04g/mL for later use.

5) Coating, setting the temperature of a front plate of a coating machine to be 43 ℃, setting the temperature of a rear plate to be 48 ℃, and preparing a film (the film thickness is controlled to be 100 mu m) at the rotating speed of 280 r/min; and (3) stripping the medicinal film from the film material after film formation to prepare the mecobalamin oral slow-release film.

6) Cut into 3cm by 2cm.

Example 5

The embodiment provides a mecobalamin oral slow-release film, which is mainly characterized in that the raw material components and the preparation method are the same as those in embodiment 1: the film former is replaced by polyvinyl alcohol.

Comparative example 1

The comparative example provides a mecobalamin oral sustained-release film, which has the main differences of the raw material components and the preparation method as in the example 1: the plasticizer is replaced with PEG400.

Comparative example 2

The comparative example provides a mecobalamin oral sustained-release film, which has the main differences of the raw material components and the preparation method as in the example 1: the binder is replaced with povidone and the plasticizer with PEG400.

Test example 1 appearance evaluation

Appearance was evaluated by flexibility, smoothness, uniformity of film color, uniformity of film. Flexibility: and (5) examining the difficulty degree of film stripping and the damage condition caused by film stripping of the film agent. The easier the stripping is, and the higher the breakage-free fraction is in the stripping process; smoothness: examining the presence or absence of bubbles and the number of small pimples, wherein the higher the bubble component value is; uniformity of film color: whether the surface color of the film agent is uniform or not is inspected, and the more uniform the surface color is, the higher the score is; uniformity of film: and (3) inspecting whether the thickness of each film obtained by cutting is consistent and the weight difference, wherein the score of the consistent thickness or the weight difference is higher, the thickness is a digital display micrometer (the measuring range is 0-25mm, the resolution is 0.001 mm), the cut film with the thickness of 3cm multiplied by 2cm is arranged between the upper layer and the lower layer of the micrometer, and the thickness of the mecobalamin oral cavity slow-release film agent at four corners and 5 different positions in the middle is measured and recorded.

The samples of examples 1-5 and comparative examples 1-2 were scored for appearance and counted according to the following criteria.

The evaluation criteria are shown in table 5:

TABLE 5 appearance evaluation basis and corresponding score

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The test results are shown in table 6:

table 6 appearance evaluation results of each example and comparative example

Note that: there were significant differences between groups labeled with different letters, p < 0.05.

Test example 2 taste evaluation

Mouthfeel was assessed by taste of 10 volunteers.

The samples of examples 1-5 and comparative examples 1-2 were scored for mouthfeel and counted according to the following criteria.

The evaluation criteria are shown in table 7:

TABLE 7 evaluation basis and corresponding score for taste evaluation

The test results are shown in table 8:

table 8 results of taste evaluation of examples and comparative examples

Sample of	Mouthfeel score (n=10)
		Example 1	4.9±0.3a
Example 2	4.8±0.4a
		Example 3	4.7±0.4a
Example 4	4.7±0.4a
		Example 5	3.6±0.6b
Comparative example 1	2.2±0.4b
		Comparative example 2	2.1±0.5b

Test example 3 number of fold resistance

The mechanical properties of the film were evaluated by repeating folding to break at the middle of the film with a size of 1cm×1 cm. Six films were tested and averaged.

The test results are shown in table 9:

table 9 evaluation results of the number of times of folding endurance of each example and comparative example

Sample of	Folding times (n=6)
		Example 1	32.6±1.6a
Example 2	29.3±2.1a
		Example 3	33.7±1.4a
Example 4	32.7±1.4a
		Example 5	22.3±1.9b
Comparative example 1	21.5±1.2b
		Comparative example 2	19.2±2.2b

Test example 4 tack measurement

The film viscosity was measured by the rubber method, two rubber sheets (2 cm. Times.3 cm) were used, one rubber sheet was fixed under the table top, the other rubber sheet was connected to the pallet balance to form an upper rubber sheet, and the balance was balanced. Taking 1 piece of film agent with the same size as the rubber, sticking the film agent on the surface of the lower rubber (the upper rubber and the lower rubber are wetted by a small amount of artificial saliva in advance), placing the upper rubber on the film, adding a weight of 2kg to press for 90s, removing the weight, adding weights, taking the upper rubber and the lower rubber within 50s as the standard, and the weight of the added weights indicates the adhesive force of the film.

The test results are shown in table 10:

table 10 weight-to-weight comparison results for each example and comparative example

Sample of	Weight of weight
		Example 1	5.3kg
Example 2	7.1kg
		Example 3	4.7kg
Example 4	5.6kg
		Example 5	5.1kg
Comparative example 1	4.2kg
		Comparative example 2	2.7kg

Test example 5 stability content determination

And (3) putting 10 pieces of each film to be tested into the condition of illumination of 5000Lux, comparing and measuring the contents of 0 day, 5 days, 10 days and 30 days, and taking an average value.

The content testing method comprises the following steps:

test solution: taking 10 pieces of film to be detected, respectively placing the film to be detected into a 100mL measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic treatment to dissolve mecobalamin, cooling, diluting to a scale with the mobile phase, shaking uniformly, filtering, and taking the subsequent filtrate as a solution of a sample.

Control solution: taking a proper amount of mecobalamin reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 50 mug in each 1 ml.

And (5) operating in a dark place. The content was determined by high performance liquid chromatography (general rule 0512).

The test results are shown in table 11:

table 11 content comparison results for each example and comparative example

Test example 6 content uniformity determination

The content testing method comprises the following steps:

Control solution: taking a proper amount of mecobalamin reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 50 mug of mecobalamin reference substance per 1 mL.

The test results are shown in tables 12 to 13:

TABLE 12 content uniformity measurement results of example 1

Sequence number	Content of
		Sample 1	96.899
Sample 2	103.253
		Sample 3	102.617
Sample 4	96.119
		Sample 5	103.643
Sample 6	99.901
		Sample 7	96.719
Sample 8	96.933
		Sample 9	97.463
Sample 10	101.697
		Average value of	99.52％
A+2.2S(≤15)	7.14

TABLE 13 content uniformity comparison results for each example and comparative example

Sequence number	A+2.2S(≤15)
		Example 1	7.14
Example 2	8.65
		Example 3	8.27
Example 4	9.23
		Example 5	16.34
Comparative example 1	18.84
		Comparative example 2	17.36

Test example 7 dissolution profile determination

(1) Instrument and reagent

Instrument: RCZ-8A intelligent drug dissolution instrument (Tianjin university precision instruments factory);

reagent: mecobalamin oral slow release film.

(2) The method comprises the following steps: and (5) operating in a dark place. The samples were taken and assayed by the release rate assay (general rule 0931, second method).

Detection wavelength: 264nm;

test parameters:

the dissolution method comprises the following steps: a paddle method;

dissolution medium: 500mL of an aqueous solution; the rotating speed is 50 revolutions per minute;

sampling time: 30min,60min,90min,2h,3h,4h,6h,8h,10h,12h.

The measurement results are shown in Table 14:

table 14 cumulative dissolution data (%)

Sequence number	30min	60min	90min	2h	3h	4h	6h	8h	10h	12h
											Example 1	15.85	27.14	33.45	47.52	68.21	85.23	93.47	99.78	98.49	100.52
Example 2	12.54	24.98	28.64	52.15	69.29	86.52	92.58	99.25	99.98	99.16
											Example 3	15.25	25.59	39.47	57.29	72.26	87.96	91.54	98.87	99.47	101.52
Example 4	14.28	25.72	37.99	55.48	70.37	88.29	94.21	99.25	98.88	99.01
											Example 5	21.26	30.85	42.44	60.21	75.64	84.65	88.13	98.47	97.58	97.82
Comparative example 1	23.46	40.56	54.87	71.28	82.25	91.57	97.56	99.87	99.28	100.26
											Comparative example 2	25.98	39.49	57.06	74.92	83.47	90.94	99.47	98.04	98.54	98.77

From the above results, it can be seen that: examples 1 to 5, by selecting proper film forming agents, adhesives, plasticizers, flavoring agents and coloring agents and combining scientific dosage proportions, the obtained mecobalamin oral slow-release film has excellent performances in aspects of appearance, mouthfeel, folding times, viscosity, stability content, content uniformity, dissolution rate and the like. Of which example 1 performed best.

The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.

The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent of the invention should therefore be determined with reference to the appended claims, which are to be construed as in accordance with the doctrines of claim interpretation.

Claims

1. The mecobalamin oral slow-release film is characterized by comprising the following raw material components in parts by weight:

2-8 parts of mecobalamin,

15-40 parts of film forming agent,

10-40 parts of adhesive and

10-30 parts of plasticizer;

wherein the adhesive is hypromellose K100M;

the plasticizer is triethyl citrate;

the film forming agent is copovidone S-630;

the raw material components also comprise a flavoring agent and a coloring agent, wherein the flavoring agent is selected from saccharin sodium, and the coloring agent is carmine;

the preparation method of the mecobalamin oral slow-release film comprises the following steps:

dissolving the mecobalamin in water to prepare a mecobalamin solution;

all the steps are carried out under red light conditions.

2. The mecobalamin oral slow-release film according to claim 1, wherein the flavoring agent is 1-10 parts by weight.

3. The mecobalamin oral slow-release film according to claim 1, wherein the colorant is 0.001-0.005 parts by weight.

4. The mecobalamin oral slow-release film according to claim 1, which is characterized by comprising the following raw material components in parts by weight:

5-7 parts of mecobalamin,

23-27 parts of film forming agent,

27-33 parts of adhesive,

17-23 parts of plasticizer,

1-10 parts of flavoring agent and

0.001 to 0.005 part of a colorant.

5. The mecobalamin oral slow-release film according to claim 4, comprising the following raw material components in parts by weight:

5-7 parts of mecobalamin,

24-26 parts of copovidone S-630,

29-31 parts of hydroxypropyl methylcellulose K100M,

19-21 parts of triethyl citrate,

8-10 parts of saccharin sodium, and

0.002-0.004 parts of carmine.

6. The mecobalamin oral slow-release film according to claim 5, comprising the following raw material components in parts by weight:

6 parts of mecobalamin,

25 parts of copovidone S-630,

Hydroxypropyl methylcellulose K100M 30 parts,

20 parts of triethyl citrate,

Saccharin sodium 9 parts, and

carmine 0.003 parts.

7. The mecobalamin oral slow-release film according to any one of claims 1-6, wherein the feed liquid ratio of the film forming agent to warm water at 50-60 ℃ is 1g (5-20) mL.

8. The mecobalamin oral slow-release film according to any one of claims 1 to 6, wherein the film forming treatment comprises the steps of:

vacuum degassing the medicine-containing solution, and then coating;

wherein the vacuum degree of vacuum degassing is more than or equal to 0.080MPa, the temperature of a front plate of a coating film is 40-45 ℃, the temperature of a rear plate of the coating film is 45-50 ℃, and the rotating speed of the coating film is 250-300 r/min.

9. The mecobalamin oral slow release film according to any one of claims 1 to 6, wherein the illuminance of red light is 1 to 5lx.

10. The mecobalamin oral slow-release film according to any one of claims 1 to 6, wherein the concentration of said mecobalamin solution is 0.02 to 0.05g/mL.