Doxylamine film agent for oral administration and preparation method of doxylamine film agent

Abstract

The embodiment of the invention discloses a doxylamine film agent for oral administration and a preparation method of the doxylamine film agent. The doxylamine film agent comprises the following components in percentage by weight: 9-40% of doxylamine succinate, 30-80% of a forming agent, 5-20% of a plasticizer, 0-20% of a crystallization inhibitor, 0-2% of a penetration enhancer, 0.5-3% of a flavoring agent, 0-5% of a pH regulator and 0-0.1% of a coloring agent. The doxylamine film agent disclosed by the invention can enable a drug to reach a plasma concentration peak value more quickly, takes effect more quickly, can maintain the total drug action amount equivalent to that of a tablet, and has a better clinical application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a doxylamine film for oral administration and its preparation method. Background Technology

[0002] Doxylamine is an antihistamine used to relieve insomnia and allergy symptoms, and is also used to treat motion sickness and seasickness. Currently, it is available in various dosage forms overseas, including tablets, capsules, granules, and oral solutions. All of these are absorbed through the gastrointestinal tract and have a slow onset of action. For example, tablets are available in strengths of 12.5 / 15 / 25mg, with an onset of action of over 30 minutes, peak effect in 2-3 hours, and a duration of action of 8-10 hours. Therefore, it should be taken 30 minutes before bedtime.

[0003] Benzodiazepines, a common treatment for insomnia Benzene and non-benzodiazepines This type of drug offers more flexible dosing options:

[0004] (1) If you expect to have difficulty falling asleep, it is recommended to take it 5 to 10 minutes before bedtime;

[0005] (2) If you cannot fall asleep within 30 minutes of going to bed, you should take the medication immediately, depending on your sleep needs at night.

[0006] (3) If you wake up at night and cannot fall back asleep and the expected wake-up time is more than 5 hours away, you can take a short half-life drug.

[0007] (4) Take before bedtime according to the needs of daytime activities the following day.

[0008] Compared to previous medications, doxylamine tablets have a longer onset time than the commonly used insomnia medications mentioned above, making it difficult to meet the principle of taking insomnia medications as needed.

[0009] Rapidly absorbed film-forming agents (also known as fast-dissolving film-forming agents or oral fast-dissolving film-forming agents) are a new type of oral solid dosage form. By dissolving or dispersing drugs in a polymeric film-forming material, they are made into thin film-like preparations that can be administered through specific sites in the oral cavity (such as under the tongue or buccal mucosa). By increasing the blood flow rate of the film and adjusting the pH of the oral film, the drug can be rapidly dissolved and absorbed.

[0010] CN200410100395.9 describes a fast-dissolving edible film containing ion exchange resin as a taste masking agent. The advantage of this technology lies only in the convenience of taking the drug, and its drug absorption speed and absorption degree are similar to those of tablets.

[0011] CN200480017592.2 describes an instant, orally disposable film containing sucralose as a sweetener. The core technology lies in the application of flavoring agents. However, given the wide variety of flavoring agents available, the technological advantage of using sucralose alone is not particularly prominent.

[0012] CN200480022053.8 describes a film containing a therapeutic agent, a digestible film suitable for dissolving in a patient's mouth, wherein the film contains nitroglycerin and a water-soluble polymer. This technology is a limitation on dosage forms, restricting almost all oral / oral-electrolyte drugs, and does not address the technological advantages and absorption characteristics related to doxylamine.

[0013] CN200580036946.2 describes a time-delayed dosage form for treating insomnia, which is suitable for releasing the drug after a lag time during which virtually no drug is released. The lag time is approximately one hour after administration. This technology creates a delayed-onset formulation that needs to be taken in advance, which does not meet the clinical requirement of on-demand administration of insomnia medications.

[0014] CN200580044597.9 describes an oral disintegrating pharmaceutical composition having a sensory cueing agent, comprising: (a) a therapeutically effective amount of at least one systemically active pharmaceutical ingredient; and (b) a sensory cueing effective amount of at least one sensory cueing agent; wherein the pharmaceutical composition is designed to disintegrate in the oral cavity in less than about 60 seconds. Since sensory cueing agents generally have a stimulating effect, they may weaken the efficacy of medications for treating insomnia.

[0015] CN201480071821.2 describes an orally disintegrating porous membrane containing a pharmacologically active ingredient and its preparation method. The orally disintegrating porous membrane comprises a foaming agent, a foam stabilizer, a plasticizer, and a pharmacologically active ingredient. The core objective of this technology is to solve the problem of uniform disintegration of drugs within a short time, while the use of a foaming agent can slightly improve the taste.

[0016] CN201611272103.9 An oral fast-dissolving film containing docetaxel succinate and pyridoxine hydrochloride, wherein the active ingredients are docetaxel succinate and pyridoxine hydrochloride.

[0017] CN201710583469.6 A dosage form for oral insertion, a pharmaceutical composition for application to the oral mucosa comprising: a water-soluble matrix, containing an effective amount of a pharmaceutically active agent and an absorption enhancer, the absorption enhancer having an HLB (sucrose fatty acid ester) of about 8 to about 16. This technology improves the permeability of the oral mucosa by using the absorption enhancer. Summary of the Invention

[0018] According to the diagnostic criteria for insomnia, an adult is considered to have insomnia if their sleep latency exceeds 30 minutes. Currently, doxylamine preparations have an onset time of approximately 30 minutes, meaning that when a patient confirms they need medication to improve their sleep, they must wait 30 minutes for the drug to take effect. Additionally, its half-life is 10 hours, and its peak time (T0) is... max The onset time is 2 hours, which is sufficient to guarantee a normal 6-8 hours of sleep in terms of duration of action. If the time to peak effect can be accelerated and the overall onset process slightly shortened, the impact of medication on daytime condition the following day can be further reduced. Therefore, the core objective of this invention is to accelerate the onset of drug action and the time to peak effect, thereby optimizing the medication experience.

[0019] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0020] According to a first aspect of the present invention, the present invention provides a doxylamine film for oral administration, comprising, by weight percentage: 9-40% doxylamine succinate, 30-80% molding agent, 5-20% plasticizer, 0-20% crystallization inhibitor, 0-2% penetration enhancer, 0.5-3% flavoring agent, 0-5% pH adjuster, and 0-0.1% colorant.

[0021] Furthermore, the molding agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, and microcrystalline cellulose.

[0022] Furthermore, the plasticizer is selected from one or more of glycerin, polyethylene glycol 300, and polyethylene glycol 400, preferably polyethylene glycol 400.

[0023] Furthermore, the crystallization inhibitor is povidone and / or cross-linked povidone, preferably povidone K90.

[0024] Furthermore, the penetration enhancer is vitamin E.

[0025] Furthermore, the flavoring agent is selected from one or more of sucralose, aspartame, steviol glycosides, maltose, and sodium saccharin, with sucralose being preferred.

[0026] Furthermore, the pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, and sodium citrate.

[0027] Furthermore, the colorant includes brilliant blue.

[0028] According to a second aspect of the present invention, the present invention provides a method for preparing the orally administered doxylamine film as described above, the method comprising:

[0029] Doxylamine succinate was mixed with purified water and stirred to dissolve. Flavoring agent, crystallization inhibitor and penetration enhancer were added in sequence and stirred to dissolve.

[0030] Add molding agent, plasticizer and colorant, stir and swell for 20-40 minutes;

[0031] Add a pH adjuster to make the pH 6-8;

[0032] Centrifugal vacuum degassing, coating and drying, and cutting are then obtained.

[0033] The embodiments of the present invention have the following advantages:

[0034] The oral doxylamine film provided by this invention uses doxylamine succinate as the active ingredient. Through extensive research on excipients, it was found that the doxylamine film, compared to ordinary tablets, has the following advantages: max Decrease, AUC (o-t) The lack of significant difference indicates that the film-forming agent of this invention allows the drug to reach peak blood concentration more quickly, resulting in faster onset of action, while maintaining a total drug effect comparable to that of tablets. Detailed Implementation

[0035] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] Example 1

[0037] This embodiment provides a doxylamine film for oral administration, the raw materials of which are as follows: 12.5g doxylamine succinate, 17g hydroxypropyl methylcellulose, 2.6g polyethylene glycol 400, 1g povidone K90, 0.01g vitamin E, 0.2g sucralose, 0.02g sodium hydroxide, 0.01g brilliant blue, and 57g purified water.

[0038] The preparation method of the above-mentioned doxylamine film includes the following steps:

[0039] (1) Mix doxylamine succinate with purified water, stir to dissolve, and then add sucralose, povidone K90 and vitamin E in sequence, stirring to dissolve.

[0040] (2) Add hydroxypropyl methylcellulose, polyethylene glycol 400 and brilliant blue, and stir to swell for 30 minutes.

[0041] (3) Add sodium hydroxide, and the pH of the system is 7.5.

[0042] (4) Centrifuge and vacuum degassing, coating and drying, cutting, and applying 500 sheets of cyclophosphamide film.

[0043] Example 2

[0044] This embodiment provides an oral doxylamine film preparation, the raw materials of which are as follows: 12.5g doxylamine succinate, 12g hydroxypropyl methylcellulose, 6.5g glycerin, 1.8g povidone K90, 0.01g vitamin E, 0.2g steviol glycosides, 0.03g sodium bicarbonate, 0.01g brilliant blue, and 57g purified water.

[0045] The preparation method of the above-mentioned doxylamine film includes the following steps:

[0046] (1) Mix doxylamine succinate with purified water, stir to dissolve, and then add steviol glycosides, povidone K90 and vitamin E in sequence, stirring to dissolve.

[0047] (2) Add hydroxypropyl methylcellulose, glycerin and brilliant blue, and stir to swell for 30 minutes.

[0048] (3) Add sodium bicarbonate, and the pH of the system is 6.8.

[0049] (4) Centrifuge and vacuum degassing, coating and drying, cutting, and applying 500 sheets of cyclophosphamide film.

[0050] Example 3

[0051] This embodiment provides a doxylamine film for oral administration, the raw materials of which are as follows: 12.5g doxylamine succinate, 15g hydroxypropyl methylcellulose, 4.6g polyethylene glycol 400, 1.2g povidone K90, 0.02g vitamin E, 0.2g sucralose, 0.04g sodium citrate, 0.01g brilliant blue, and 57g purified water.

[0052] The preparation method of the above-mentioned doxylamine film includes the following steps:

[0053] (1) Mix doxylamine succinate with purified water, stir to dissolve, and then add sucralose, povidone K90 and vitamin E in sequence, stirring to dissolve.

[0054] (2) Add hydroxypropyl methylcellulose, polyethylene glycol 400 and brilliant blue, and stir to swell for 30 minutes.

[0055] (3) Add sodium citrate, and the pH of the system is 7.2.

[0056] (4) Centrifuge and vacuum degassing, coating and drying, cutting, and applying 500 sheets of cyclophosphamide film.

[0057] Example 4

[0058] This embodiment provides a doxylamine film for oral administration, the raw materials of which are as follows: 12.5g doxylamine succinate, 17g hydroxypropyl methylcellulose, 2.6g polyethylene glycol 400, 0.2g sucralose, 0.01g vitamin E, 0.02g sodium hydroxide, 0.01g brilliant blue, and 57g purified water.

[0059] The preparation method of the above-mentioned doxylamine film includes the following steps:

[0060] (1) Mix doxylamine succinate with purified water, stir to dissolve, then add sucralose and vitamin E in sequence, and stir to dissolve;

[0061] (2) Add hydroxypropyl methylcellulose, polyethylene glycol 400 and brilliant blue, and stir to swell for 30 minutes.

[0062] (3) Add sodium hydroxide, and the pH of the system is 7.5.

[0063] (4) Centrifuge and vacuum degassing, coating and drying, cutting, and applying 500 sheets of cyclophosphamide film.

[0064] Example 5

[0065] This embodiment provides a doxylamine film for oral administration, the raw materials of which are as follows: 12.5g doxylamine succinate, 17g hydroxypropyl methylcellulose, 1.2g polyethylene glycol 400, 1g povidone K90, 0.2g sucralose, 0.02g sodium hydroxide, 0.01g brilliant blue, and 57g purified water.

[0066] The preparation method of the above-mentioned doxylamine film includes the following steps:

[0067] (1) Mix doxylamine succinate with purified water, stir to dissolve, then add sucralose and povidone K90 in sequence, and stir to dissolve.

[0068] (2) Add hydroxypropyl methylcellulose, polyethylene glycol 400 and brilliant blue, and stir to swell for 30 minutes.

[0069] (3) Add sodium hydroxide, and the pH of the system is 7.5.

[0070] (4) Centrifuge and vacuum degassing, coating and drying, cutting, and applying 500 sheets of cyclophosphamide film.

[0071] Test Example 1

[0072] The pharmacokinetics of the orally administered doxylamine film provided in Examples 1-5 were investigated, and compared with doxylamine tablets (ILKO, Türkiye). The time to peak concentration (T0) was measured. max ) and area under the plasma concentration-time curve (AUC)(0-t) The test results are shown in Table 1 below.

[0073] Table 1

[0074] sample <![CDATA[T max (h)]]> <![CDATA[AUC (0-t) (ng / ml h)]]> Example 1 0.89 1683 Example 2 1.02 1645 Example 3 1.13 1663 Example 4 1.34 1608 Example 5 1.25 1637 Doxylamine tablets 1.50 1627

[0075] The results showed that the doxylamine film provided in this embodiment of the invention had a significantly reduced time to peak concentration and lower AUC compared to existing doxylamine tablets. (0-t) There was no significant difference. The above content indicates that the doxylamine film of the present invention can reach the peak blood concentration more quickly, thereby achieving a faster onset of action.

[0076] Based on clinical trials, the statistical results of the onset time of the doxylamine film provided in this embodiment of the invention are shown in Table 2 below.

[0077] Table 2

[0078] sample Onset time (min) Example 1 15±1.6 Example 3 21±2.0 Example 5 24±1.8 Doxylamine tablets 30±2.1

[0079] The results showed that, compared with existing doxylamine tablets, the doxylamine film provided in this embodiment of the invention significantly shortened the time it took for the drug to help the subjects fall asleep.

[0080] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A doxylamine film for oral administration, characterized in that, The product comprises the following components by weight percentage: doxylamine succinate 9-40%, molding agent 30-80%, plasticizer 5-20%, crystallization inhibitor 0-20%, penetration enhancer 0-2%, flavoring agent 0.5-3%, pH adjuster 0-5%, and colorant 0-0.1%.

2. The orally administered doxylamine film according to claim 1, characterized in that, The molding agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 6000, and microcrystalline cellulose.

3. The orally administered doxylamine film according to claim 1, characterized in that, The plasticizer is selected from one or more of glycerin, polyethylene glycol 300, and polyethylene glycol 400.

4. The doxylamine film agent according to claim 1, characterized in that, The crystallization inhibitor is povidone and / or cross-linked povidone.

5. The orally administered doxylamine film according to claim 1, characterized in that, The penetration enhancer is vitamin E.

6. The orally administered doxylamine film according to claim 1, characterized in that, The flavoring agent is selected from one or more of sucralose, aspartame, steviol glycosides, maltose, and sodium saccharin.

7. The orally administered doxylamine film according to claim 1, characterized in that, The pH adjuster is selected from one or more of sodium hydroxide, sodium bicarbonate, and sodium citrate.

8. The orally administered doxylamine film according to claim 1, characterized in that, The colorant includes brilliant blue.

9. The method for preparing the oral doxylamine film according to claim 1, characterized in that, The method includes: Doxylamine succinate was mixed with purified water and stirred to dissolve. Flavoring agent, crystallization inhibitor and penetration enhancer were added in sequence and stirred to dissolve. Add molding agent, plasticizer and colorant, stir and swell for 20-40 minutes; Add a pH adjuster to make the pH 6-8; Centrifugal vacuum degassing, coating and drying, and cutting are then obtained.