Vitamin D3 nano-emulsion oral instant film and preparation method thereof

Abstract

The invention discloses a vitamin D3 nano-emulsion oral instant film composition and a preparation method thereof. The vitamin D3 nano-emulsion oral instant film disclosed by the invention is rapidly disintegrated in the oral cavity, does not need to drink water, is high in bioavailability, convenient to swallow, suitable for children, old people and the like, and high in medication compliance; the oral instant film can solve the problem that the dosage of oral solution is not accurate. The vitamin D3 is prepared into the nano-emulsion, so that oxidative degradation of the vitamin D3 is effectively slowed down, the drug loading capacity is increased, and the bioavailability is improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a vitamin D3 nanoemulsion orally disintegrating film and a preparation method thereof. Background Art

[0002] Vitamin D3 plays important roles such as promoting calcium absorption, inducing calcium and phosphorus deposition, and preventing rickets. However, there is a widespread phenomenon of vitamin D3 deficiency among the general population, and a large number of people need to supplement vitamin D3 additionally, especially children need to supplement vitamin D3 from birth. To meet the human body's demand for vitamin D3 supplementation, industry technical researchers have developed preparations such as vitamin D3 drops, calcium carbonate-vitamin D3 compound oral solid preparations (including granules, tablets, chewable tablets, etc.), and alendronate sodium vitamin D3 tablets. However, traditional vitamin D3 tablets or capsules have the problem of difficult swallowing, and children have poor compliance; when made into liquid preparations, due to the sensitivity of vitamin D3 to light, oxygen, and acid, there are problems of easy oxidation and degradation, and inaccurate dosing. Therefore, the industry needs to provide a pharmaceutical composition containing vitamin D3 with good long-term stability, high uniformity, simple preparation, and low cost, as well as a preparation method thereof.

[0003] After extensive literature research, there has been no report on calcium supplementation products in the form of orally disintegrating thin films in China so far. Therefore, the research on preparing vitamin D3 into an orally disintegrating thin film preparation has very profound significance. The orally disintegrating film is a safe and effective dosage form. Compared with traditional tablets, capsules, granules, etc., because it can dissolve rapidly in the mouth and does not require drinking water when taking, it has the advantages of rapid onset, high bioavailability, convenient carrying and use.

[0004] In summary, the raw material of vitamin D3 has poor stability. When made into a nanoemulsion and the drug is encapsulated in the emulsion film, the nanoemulsion can play the role of an "isolating coat" and increase the stability of the drug; moreover, the dosage form of vitamin D3 is small, and making it into an orally disintegrating film can fully meet the drug loading requirements, increase the drug loading amount, and improve the bioavailability; and the orally disintegrating film has accurate dosing, small volume, and successfully masks the taste, with a good taste, especially suitable for children and the elderly to take, thus meeting the vitamin D3 supplementation needs of such populations and having broad market promotion advantages. Summary of the Invention

[0005] Aiming at the deficiencies of the prior art, the present invention provides a composition of a vitamin D3 nanoemulsion orally disintegrating film and a preparation method thereof.

[0006] The technical solution of the present invention is as follows: A composition of a vitamin D3 nanoemulsion orally disintegrating film, characterized in that, by mass percentage, it includes:

[0007] Vitamin D3 nanoemulsion: 5 - 10%

[0008] Film-forming matrix: 60-90%

[0009] Flavoring agent: 5-15%

[0010] Plasticizer: 10-15%

[0011] Among them, the film-forming matrix is polyethylene glycol and pectin, and the weight ratio of polyethylene glycol to pectin is 3:1 to 5:1, preferably 4:1; Vitamin D3 nanoemulsion: It is composed of vitamin D3, medium-chain triglyceride, antioxidant and compound emulsifier. The polyethylene glycol is preferably one or more of PEG1000, PEG2000 or PEG3350.

[0012] In some embodiments, the compound emulsifier is selected from at least one of phospholipid, poloxamer, Tween 80, Span 80, and gum arabic. Preferably, it is phospholipid and poloxamer 188, and the weight ratio of phospholipid to poloxamer 188 is 2:1 to 4:1. More preferably, the weight ratio of phospholipid to poloxamer 188 is 3:1.

[0013] In some embodiments, the flavoring agent is sucralose and / or stevioside.

[0014] In some embodiments, the plasticizer is glycerol.

[0015] In some embodiments, the antioxidant is vitamin E.

[0016] The preparation method of the vitamin D3 nanoemulsion orally disintegrating film provided by the present invention is characterized in that the preparation method includes the following steps:

[0017] (1) Dissolve vitamin D3 and antioxidant in medium-chain triglyceride (MCT), add the compound emulsifier aqueous phase, and perform high-pressure homogenization to obtain vitamin D3 nanoemulsion, controlling the nanoemulsion particle size ≤ 100 nm;

[0018] (2) Dissolve the film-forming matrix in pure water, add the plasticizer, cool after dissolution, add the nanoemulsion and the flavoring agent, and degas after complete swelling;

[0019] (3) Coat on a coater, dry with hot air, control the dry film thickness to be 80-120 μm, cut into single-dose film tablets and package to obtain the vitamin D3 nanoemulsion orally disintegrating film (each tablet contains 400 IU of vitamin D3);

[0020] Preferably, the high-pressure homogenization pressure is 600-1000 bar, preferably 600-800 bar.

[0021] The disintegration time of the vitamin D3 nanoemulsion orally disintegrating film described in this product is ≤ 30 s. Detailed implementation mode

[0022] The following embodiments can enable those skilled in the art of this specialty to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described embodiments.

[0023] Example 1

[0024] Dissolve vitamin D3 and vitamin E in medium-chain triglyceride (MCT) at 60 °C according to Table 1 below, add the emulsifier aqueous phase, and homogenize at 800 bar for 3 cycles to obtain vitamin D3 nanoemulsion. The particle size of the nanoemulsion is controlled below 100 nm. Dissolve polyethylene glycol and pectin in pure water at 60 °C, add glycerol, cool to 40 °C after dissolution, add the nanoemulsion, sucralose and stevioside, and degas after complete swelling. Coat on a coater and dry at 50 °C with hot air for 10 min, control the dry film thickness to be 80 - 120 μm, cut into single-dose film tablets and package to obtain the oral fast-dissolving film of vitamin D3 nanoemulsion (each tablet contains 400 IU of vitamin D3).

[0025] Table 1

[0026]

[0027] Example 2

[0028] The preparation method is as described in Example 1, and the specific prescription composition is shown in Table 2 below.

[0029] Table 2

[0030]

[0031] Example 3

[0032] The preparation method is as described in Example 1, and the specific prescription composition is shown in Table 3 below.

[0033] Table 3

[0034]

[0035] Example 4

[0036] The preparation method is as described in Example 1, and the specific prescription composition is shown in Table 4 below.

[0037] Table 4

[0038]

[0039] Example 5

[0040] The preparation method is as described in Example 1, and the specific prescription composition is shown in Table 5 below.

[0041] Table 5

[0042]

[0043] Example 6

[0044] The preparation method is shown in Example 1, and the specific prescription composition is shown in Table 6 below.

[0045] Table 6

[0046]

[0047] Example 7

[0048] The preparation method is shown in Example 1, and the specific prescription composition is shown in Table 7 below.

[0049] Table 7

[0050]

[0051] Example 8

[0052] The specific prescription composition is shown in Example 1. In the preparation method, the high-pressure homogenization pressure is 600 bar and the cycle is 2 times. The particle size of the vitamin D3 nanoemulsion obtained is 150 nm ± 10 nm; other conditions are the same as in Example 1.

[0053] For Examples 1 - 8 of the present invention, the uniformity, tensile strength, and elongation at break of the film agents were measured, and the results are shown in Table 8 below; the disintegration time limit was measured; the samples were placed at a temperature of 40 °C and a humidity of 75% RH for 1 month and 3 months, and the content and peroxide value were detected; the results are shown in Table 9 below.

[0054] Table 8

[0055]

[0056] Table 9

[0057]

[0058] Conclusion: The results of performance, disintegration time limit, and stability show that in Example 1, the emulsifiers selected are polyethylene glycol and pectin, and the ratio is 4:1; in Example 2, the ratio of polyethylene glycol to pectin is 3:1. Example 2 has poorer tensile strength, lower elongation at break, and a longer disintegration time limit than Example 1; in Example 3, the ratio of polyethylene glycol to pectin is 5:1, and the stability is poorer than that of Example 1; therefore, it is more preferable to choose a ratio of polyethylene glycol to pectin of 4:1;

[0059] In Example 4, the emulsifier selected is Tween 80, and the performance of the quick-dissolving film is good, but the disintegration time limit is longer than that of Example 1, and the stability result is poor; therefore, the preferred emulsifiers are phospholipid and poloxamer 188.

[0060] In Example 1, the glycerol proportion was selected as 12%. In Example 5, the glycerol proportion was selected as 6%, with a worse tensile strength, lower elongation at break, and longer disintegration time limit compared to Example 1. In Example 6, the glycerol proportion was selected as 18%, with worse stability compared to Example 1. Therefore, the preferred dosage of the plasticizer glycerol is 12%.

[0061] Compared with Example 1, the dosage of the antioxidant vitamin E in Example 7 was reduced, with no significant difference in the disintegration time limit and worse stability results. However, considering that it is not advisable to add too much antioxidant, the preferred addition amount of vitamin E is 0.1%.

[0062] Compared with Example 1, the nanoemulsion particle size in Example 8 was controlled at about 150 nm, the uniformity of the film agent was average, and the disintegration time limit was longer. Therefore, the nanoemulsion particle size is preferably controlled within 100 nm, and the high-pressure homogenization pressure is controlled at 800 bar for 3 cycles.

[0063] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not restrictive. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and all should be covered within the scope of the claims of the present invention.

Claims

1. A vitamin D3 nanoemulsion orally disintegrating film, characterized in that, Comprising, by mass percentage: Vitamin D3 nanoemulsion: 5 - 10% Film-forming matrix: 60 - 90% Flavoring agent: 5 - 15% Plasticizer: 10 - 15% Among them, the film-forming matrix is polyethylene glycol and pectin, and the weight ratio of polyethylene glycol to pectin is 3:1 to 5:1, preferably 4:1; the vitamin D3 nanoemulsion is prepared from vitamin D3, medium-chain triglyceride (MCT), antioxidant and composite emulsifier, and the composite emulsifier is selected from one or more of phospholipid, poloxamer, Tween 80, Span 80, gum arabic; preferably, the polyethylene glycol is selected from one or more of PEG1000, PEG2000 or PEG3350.

2. The oral fast-dissolving film of vitamin D3 nanoemulsion according to claim 1, characterized in that, The composite emulsifier is phospholipid and poloxamer 188. Preferably, the weight ratio of the phospholipid to poloxamer 188 is 2:1 to 4:1, more preferably 3:

1.

3. A vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 1-2, characterized in that, The flavoring agent is selected from at least one of sucralose, aspartame, sodium saccharin, stevioside.

4. A vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 1 to 3, characterized in that, The plasticizer is selected from at least one of glycerol and polyethylene glycol 400. Preferably, the dosage of the plasticizer is 12%.

5. A vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 1-4, characterized in that, The antioxidant is selected from at least one of vitamin E and disodium EDTA. Preferably, the dosage of the antioxidant is 0.1%.

6. An orally disintegrating film of vitamin D3 nanoemulsion according to any one of claims 1 - 5, characterized in that Vitamin D3 0.1 - 0.3% Medium-chain triglyceride 2 - 3% Composite emulsifier 3 - 5% Film-forming matrix 70% - 80% Plasticizer 12% Flavoring agent 5% - 10% Antioxidant 0.1%.

7. A vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 1-6, characterized in that, The preparation method of the vitamin D3 nanoemulsion comprises the following steps: dissolving vitamin D3 and antioxidant in medium-chain triglyceride (MCT), adding the emulsifier aqueous phase, and performing high-pressure homogenization at 600 - 800 bar for 2 - 3 cycles to obtain the vitamin D3 nanoemulsion. Preferably, the high-pressure homogenization condition is 800 bar and the high-pressure homogenization is performed 3 times.

8. A preparation method of a vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 1 to 7, characterized in that, The preparation method comprises the following steps: (1) Dissolve vitamin D3 and antioxidant in MCT, add the composite emulsifier aqueous phase after dissolution, and perform high-pressure homogenization to obtain the vitamin D3 nanoemulsion, controlling the particle size of the nanoemulsion ≤ 100 nm; (2) Dissolve the film-forming matrix in pure water, add the plasticizer, cool after dissolution, add the nanoemulsion and the flavoring agent, and degas after complete swelling; (3) Coat on a coater, dry with hot air, control the dry film thickness to be 80 - 120 μm, cut into single-dose film tablets and package to obtain the orally disintegrating film of vitamin D3 nanoemulsion.

9. The preparation method of a vitamin D3 nanoemulsion orally disintegrating film according to claim 8, characterized in that, The high-pressure homogenization condition is high-pressure homogenization at 600 - 800 bar for 2 - 3 cycles, preferably high-pressure homogenization at 800 bar for 3 cycles.

10. The preparation method of a vitamin D3 nanoemulsion orally disintegrating film according to any one of claims 8-9, characterized in that: In step 1, dissolve vitamin D3 and antioxidant in MCT at 50 - 60 °C, in step 2, dissolve the film-forming matrix in pure water at 50 - 60 °C and / or in step 3, the hot air drying condition is 50 - 60 °C for 10 - 15 min.

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