Oral film with customizable drug release curve and preparation method thereof

Abstract

The present invention discloses an oral film with a customizable drug release curve and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The preparation method of the oral film comprises: (1) preparing a double-layer drug film including a barrier layer and a drug sustained-release layer, wherein the barrier layer is a metal film capable of reacting with an acidic solution, the drug sustained-release layer comprises a water-soluble small molecule drug and a sustained-release polymer, and the drug sustained-release layer is edge-sealed and fixed on the barrier layer; (2) folding the double-layer drug film to obtain an oral film with an origami structure, realizing the customization of the drug release curve of the oral film, and preparing the oral film with a customizable drug release curve. The oral film can customize the drug release curve, improve patient compliance, and reduce health risks and medical costs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an oral film with a customizable drug release curve and a preparation method thereof. Background Art

[0002] Among the many factors that affect drug efficacy, patient non-compliance is a common problem. Patients forgetting to take medication, worrying about side effects, and doubting the effectiveness of treatment may lead to patients not following doctor's orders. Patient non-compliance will not only prolong the course of the disease and aggravate the condition, but also bring unnecessary burdens to the medical system. In pharmacology, the most effective way to improve patient compliance is to reduce the frequency of medication. A variety of drug sustained-release materials have been developed on the market, such as microcapsules, nanoparticles, and gels, to achieve the drug concentration required for long-term treatment in the body. Commercially available oral preparations such as ER and Etc., a single dose can provide 5-9 hours of drug release.

[0003] The Chinese patent document with publication number CN105769773A discloses a loxoprofen sodium sustained-release micro-pellet, which consists of a drug-loaded pellet core, an isolation layer wrapped on the drug-loaded pellet core, and a sustained-release layer wrapped on the isolation layer. When water-soluble drugs are coated with aqueous dispersions to prepare sustained-release micro-pellets, a relatively serious burst release phenomenon often occurs. The invention first coats the isolation layer on the pellet core with an acidic isolation liquid, and then coats the sustained-release layer with an aqueous dispersion, thereby reducing the burst release phenomenon, achieving good sustained-release drug release characteristics, and improving patient compliance with medication.

[0004] The Chinese patent document with publication number CN116003632A discloses a long-acting sustained-release human recombinant growth hormone fusion protein and its pharmaceutical composition and application. The corresponding growth hormone fusion protein contains growth hormone and a thermosensitive elastin-like polypeptide. After subcutaneous injection, the fusion protein will undergo a phase change in situ under the triggering of body temperature and precipitate to form a drug reservoir. The drug will be slowly released from the reservoir to the body's circulatory system, realizing that growth hormone can be continuously and slowly released in vivo without relying on microsphere preparations and chemical modification technology, significantly prolonging the effective action time of a single injection of growth hormone and improving patient compliance.

[0005] However, the above-mentioned drug sustained-release materials and methods have limited control over the drug release time, and the pre-set drug release duration may not meet the needs of each individual patient. Moreover, the above-mentioned sustained-release method can only be used for the sustained release of specific drug molecules and is not universal. In addition, it is difficult to cope with changes in the patient's condition and some rhythmic diseases. Therefore, it is of great significance to develop drug preparations that can dynamically adapt to individual circadian rhythms and pathological characteristics. Summary of the invention

[0006] In view of the shortcomings of the prior art, based on the origami principle and the prediction of the drug release process, the present invention provides a method for preparing an oral film dosage form with a customizable drug release curve, aiming to improve patient compliance and reduce health risks and medical costs.

[0007] The specific technical solutions adopted are as follows:

[0008] A method for preparing an oral film with a customizable drug release profile comprises the following steps:

[0009] (1) preparing a double-layer drug film including a barrier layer and a drug sustained-release layer, wherein the barrier layer is a metal film capable of reacting with an acidic solution, the drug sustained-release layer includes a water-soluble small molecule drug and a sustained-release polymer, and the drug sustained-release layer is edge-sealed and fixed on the barrier layer;

[0010] (2) folding the double-layer drug film to obtain an oral film with an origami structure, thereby achieving customization of the drug release curve of the oral film, and preparing the oral film with a customizable drug release curve;

[0011] In the in vitro model, the tailored drug release profile was expressed as:

[0012]

[0013] In formula (I), c t represents the drug concentration released at time t, n represents the number of pulses of drug release, M i represents the drug amount in the i-th layer, where h i and h j They represent the thickness of the barrier layer before drug release in the i-th and j-th layers, respectively. k1 and k2 are the fitting parameters for the specific barrier layer.

[0014] Furthermore, in the in vivo model, the tailored drug release profile was expressed as:

[0015]

[0016] In formula (II), c t represents the drug concentration released at time t, n represents the number of pulses of drug release, M i represents the drug amount in the i-th layer, where h i and h j They represent the thickness of the barrier layer before drug release in the i-th and j-th layers, respectively. k1 and k2 are fitting parameters for specific barrier layers. k3 is a parameter related to the metabolic rate of water-soluble small molecule drugs in vivo.3i Represents the parameters related to the in vivo metabolic rate of the i-th layer water-soluble small molecule drugs.

[0017] Specifically, the metal film can react with gastric juice, including but not limited to magnesium film, magnesium-aluminum alloy film, magnesium-lithium alloy film, zinc film, etc.

[0018] Preferably, the thickness of the metal film does not exceed 200 microns, more preferably 50-200 microns.

[0019] Specifically, the water-soluble small molecule drugs include doxofylline, hydrocortisone, metformin, nifedipine, caffeine, doxazosin, amiloride or clonidine; the sustained-release polymer includes polycaprolactone, polyvinyl alcohol, polylactic acid, pectin, polylactic acid-glycolic acid copolymer, chitosan, polyvinyl pyrrolidone or hydroxypropyl methylcellulose.

[0020] Preferably, in the drug sustained-release layer, the mass ratio of the water-soluble small molecule drug to the sustained-release polymer is 1:5-100.

[0021] Preferably, the drug sustained-release layer is edge-sealed and fixed to the barrier layer using a biosafety material, and the biosafety material can be a cellulose-based double-sided tape.

[0022] Preferably, a plurality of double-layered origami structures are formed during the folding process.

[0023] The present invention also provides an oral film prepared by the preparation method of the oral film with customizable drug release curve. The oral film has an origami structure and can be directly orally taken orally or filled into an empty capsule for oral use.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention prepares an oral film with an origami structure by folding a double-layer drug film. By adjusting the thickness, type and other parameters of the barrier layer in the double-layer drug film, and adjusting the material type, thickness, ratio and other parameters of the drug sustained-release layer, the drug release rate and the release time can be controlled. Based on the origami principle and the prediction of the drug release process, a personalized drug release curve can be achieved according to different diseases and patient needs; patients can choose the most suitable drug release rate and time according to their own condition and needs, improve the patient's acceptance and compliance to the drug, and thus improve the treatment effect; by accurately controlling the drug release rate and time, the concentration fluctuation of the drug in the body can be reduced, the incidence of drug toxicity and adverse reactions can be reduced, and the risk of drug poisoning caused by excessive or too fast release of the drug can be avoided, and the patient's medication safety can be improved; it can also avoid re-visiting and drug replacement caused by drug incompatibility or poor effect, and further reduce medical costs; the present invention can slowly release the drug in the body and prolong the drug's action time. In this way, the frequency of medication can be reduced and the convenience and comfort of patients can be improved; the production process of the oral film involved in the present invention is relatively simple, which can reduce production costs and improve production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Flow chart for the preparation of oral films with customizable drug release profiles based on origami principles.

[0027] Figure 2 This is a verification result diagram of the effect of barrier layer thickness on drug release curve.

[0028] Figure 3 This is the drug release curve verification result diagram of the oral film. A and B are the drug release curves and fitting curves of the double-layer drug film after single and double folding, respectively.

[0029] Figure 4 This is the drug release curve verification result diagram of the oral film. A and B are the drug release curve and fitting curve after the double-layer drug film was folded three times and four times, respectively.

[0030] Figure 5 The diagram shows the effect of the oral film prepared in Example 2-5 on treating rhythmic diseases, wherein A represents asthma, B represents adrenocortical insufficiency, C represents diabetes, and D represents hypertension. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with the embodiments and drawings. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0032] Preparation method of oral film with customizable drug release profile Figure 1 As shown, specifically including:

[0033] (1) selecting a water-soluble small molecule drug, a metal film and a sustained-release polymer, preparing the sustained-release polymer into a sustained-release polymer solution, fully mixing the water-soluble small molecule drug and the sustained-release polymer solution in a certain ratio to prepare a mixed solution, customizing the thickness of the metal film, and removing the surface oxide layer thereof by grinding, coating the mixed solution on the treated metal film according to the required drug amount, standing to dry to form a drug sustained-release layer, and then using a commercially available cellulose-based double-sided tape to seal the edge of the drug sustained-release layer and fix it on the metal film to prevent drug leakage from the edge, thereby preparing a double-layer drug film;

[0034] (2) folding the double-layer drug film to obtain an oral film with an origami structure, thereby achieving customization of the drug release curve of the oral film, and preparing the oral film with a customizable drug release curve;

[0035] In the in vitro model, the tailored drug release profile was expressed as:

[0036]

[0037] In formula (I), c t represents the drug concentration released at time t, n represents the number of pulses of drug release, M i represents the drug amount in the i-th layer, where h i and h j represent the barrier layer thickness before drug release of layer i and layer j respectively (when n=1, h j =0), k1 and k2 are fitting parameters for a specific barrier layer.

[0038] In the in vivo model, the tailored drug release profile was expressed as:

[0039]

[0040] In formula (II), c t represents the drug concentration released at time t, n represents the number of pulses of drug release, M i represents the drug amount in the i-th layer, where h i and h j represent the barrier layer thickness before drug release of layer i and layer j respectively (when n=1, h j =0), k1 and k2 are fitting parameters for specific barrier layers, k3 is a parameter related to the metabolic rate of water-soluble small molecule drugs in vivo, and k 3i Represents the parameters related to the in vivo metabolic rate of the i-th layer water-soluble small molecule drugs.

[0041] The oral film is put into a capsule for oral administration. Through the above method, the drug release kinetics can be adjusted to achieve personalized customization of drug release.

[0042] Example 1 Drug Release Curve Verification

[0043] A metal magnesium film is selected as a barrier layer, rhodamine B simulates a water-soluble small molecule drug, and polyvinyl alcohol is used as a sustained-release polymer. Rhodamine B and polyvinyl alcohol aqueous solution are mixed to prepare a mixed solution, and the mixed solution is coated on the metal magnesium film according to the required drug amount, and the mixed solution is left to dry to form a drug sustained-release layer. Then, a commercially available cellulose-based double-sided tape is used to seal the edge of the drug sustained-release layer and fix it on the metal magnesium film to prevent drug leakage from the edge, thereby preparing a double-layer drug film;

[0044] The double-layer drug film was folded as needed, and then placed in 100 ml of pH 1.5 hydrochloric acid solution (in vitro model). The drug dissolution experiment was carried out at 37°C and 100 rpm. 200 microliters of solution were taken from the solution every 15 minutes, and the drug concentration was finally detected by an enzyme marker. The experiment proved that the area, shape, number of drug layers and other parameters of the magnesium film had negligible effects on drug dissolution, but the thickness of the magnesium film affected the delayed release time of the drug ( Figure 2 ).like Figure 3 A and B in Figure 4 As shown in A and B in the figure, after the double-layer drug film is folded once (the number of pulses of drug release n=1), twice (the number of pulses of drug release n=2), three times (the number of pulses of drug release n=3), and four times (the number of pulses of drug release n=4), the actual drug release curves have a high degree of fit with the customized drug release curves, which proves the effectiveness of the design.

[0045] Example 2

[0046] For asthma, doxofylline was selected as a drug, a 0.2 mm metal magnesium film was used as a barrier layer, and polyvinyl alcohol was used as a sustained-release polymer. Doxofylline and a 10 wt% polyvinyl alcohol aqueous solution were mixed, and the mass ratio of doxofylline to polyvinyl alcohol was 1:10 to prepare a mixed solution. The mixed solution was coated on the metal magnesium film according to the required amount of drug, and the drug sustained-release layer was formed after standing and drying. Then, a commercially available cellulose-based double-sided tape was used to seal the edge of the drug sustained-release layer and fix it on the metal magnesium film to prevent drug leakage from the edge, and a double-layer drug film with a thickness of 500 microns was prepared.

[0047] Asthma patients are usually prone to attacks between 2 and 6 a.m., so it is designed that patients can take the drug before falling asleep normally (22:00), and the drug is delayed for 4 hours, represented by a step-format curve, and key parameters Δt and Δc are determined. Based on this, the double-layer drug film is folded once to obtain an origami-structured oral film (the folding direction is from the metal barrier layer to the drug sustained-release layer), and the oral film drug release curve is customized, and the oral film with a customizable drug release curve is prepared.

[0048] In formula (I) corresponding to the in vitro model, n=1, h1=0.2 mm, k1=1320.47 min / mm, k2=75.94 min / mm.

[0049] like Figure 5 As shown in A in the figure, the in vitro drug dissolution experiment proves that the oral film can release the drug 4 hours after taking it, effectively preventing asthma attacks in the early morning, reducing the number of medications, reducing the toxic and side effects of the drug, and improving patient compliance.

[0050] Example 3

[0051] For adrenal insufficiency, hydrocortisone was selected as a drug, a 0.1 mm metal magnesium film was used as a barrier layer, and polyvinyl alcohol was used as a sustained-release polymer. Hydrocortisone and a 10 wt% polyvinyl alcohol aqueous solution were mixed, and the mass ratio of hydrocortisone to polyvinyl alcohol was 1:5 to prepare a mixed solution. The mixed solution was coated on the metal magnesium film according to the required amount of drug, and the drug sustained-release layer was formed after standing and drying. Then, a commercially available cellulose-based double-sided tape was used to seal the edge of the drug sustained-release layer and fix it on the metal magnesium film to prevent drug leakage from the edge, and a double-layer drug film with a thickness of 900 microns was prepared.

[0052] Patients with adrenocortical insufficiency usually need to take medicine according to the time of human adrenaline secretion. Usually, they take medicine twice at 9 am and 13 pm, with an interval of about 4 hours, which is represented by a step-format curve to determine key parameters Δt and Δc, etc. Based on this, the double-layer drug film is folded twice to obtain an origami-structured oral film (the double-layer drug film is divided into two sections of 6:4, and folded from the drug sustained-release layer to the metal barrier layer, and then the smaller half of the film is folded from the metal barrier layer to the drug sustained-release layer, and the drug-exposed side is used as the dissolving front side, and the back side is sealed with a cellulose-based tape), so as to achieve the customization of the drug release curve of the oral film, and prepare the oral film with a customizable drug release curve.

[0053] In the corresponding formula (I), n = 2, h1 = 0 mm, h2 = 0.2 mm, k1 = 1320.47 min / mm, k2 = 75.94 min / mm. Figure 5As shown in B, the in vitro drug dissolution experiment proves that the oral film can release the drug for the first time after taking it, and release the drug for the second time after 4 hours. The oral film can be taken in the morning and release the drug for the second time at noon, which can fit the release rhythm of human adrenaline, improve drug efficiency and reduce drug toxicity.

[0054] Example 4

[0055] For diabetes, metformin was selected as the drug, 0.1 mm metal magnesium film was used as the barrier layer, and polyvinyl alcohol was used as the sustained-release polymer. Metformin and 10 wt% polyvinyl alcohol aqueous solution were mixed, and the mass ratio of metformin to polyvinyl alcohol was 1:10 to prepare a mixed solution. The mixed solution was coated on the metal magnesium film according to the required amount of drug (the metal magnesium film was divided into three sections of equal length, and the mixed solution was coated on different surfaces of the two sections near the edge), and the drug sustained-release layer was formed after standing and drying. Then, the drug sustained-release layer was sealed and fixed on the metal magnesium film using a commercially available cellulose-based double-sided tape to prevent drug leakage from the edge, and a double-layer drug film with a thickness of 900 microns was prepared.

[0056] Diabetic patients usually take medicine before meals, and the time interval between lunch and dinner is usually about 5-6 hours, so the interval between two doses is also 5-6 hours, which is represented by a step-format curve to determine key parameters Δt and Δc, etc. Based on this, the double-layer drug film is folded twice to obtain an origami-structured oral film (both folding directions are from the drug sustained-release layer to the metal barrier layer, and the drug-exposed side is used as the dissolving front side, and the other drug-exposed side is sealed with a cellulose-based tape), so as to achieve the customization of the oral film drug release curve, and prepare the oral film with a customizable drug release curve.

[0057] In the corresponding formula (I), n=2, h1=0 mm, h2=0.3 mm, k1=1320.47 min / mm, k2=75.94 min / mm.

[0058] like Figure 5 As shown in C, the in vitro drug dissolution experiment proves that the oral film can release the drug for the first time after taking it, and release the drug for the second time after 6 hours. The oral film can be taken before lunch and release the drug for the second time before dinner. The hypoglycemic drug that needs to be taken before or after meals is prepared into one film, which reduces the number of times the drug is taken and improves patient compliance.

[0059] Example 5

[0060] For hypertension, nifedipine was selected as the drug, a 0.1 mm metal magnesium film was used as the barrier layer, and polyvinyl alcohol was used as the sustained-release polymer. Nifedipine and a 10 wt% polyvinyl alcohol aqueous solution were mixed, and the mass ratio of nifedipine to polyvinyl alcohol was 1:10 to prepare a mixed solution. The mixed solution was coated on the metal magnesium film according to the required amount of drug, and the drug sustained-release layer was formed after standing and drying. Then, a commercially available cellulose-based double-sided tape was used to seal the edge of the drug sustained-release layer and fix it on the metal magnesium film to prevent drug leakage from the edge, and a double-layer drug film with a thickness of 900 microns was prepared.

[0061] Hypertensive patients usually need to take medication three times a day, with an interval of 4 hours between each medication, which is represented by a step-format curve to determine key parameters such as Δt and Δc. Based on this, the double-layer drug film is folded twice to obtain an oral film with an origami structure (the double-layer drug film is divided into three equal-length segments, and then the first and last segments are folded toward the middle, and the folding direction is from the drug sustained-release layer to the metal barrier layer, and the middle layer is used as the dissolving front side, and the back side is sealed with a cellulose-based tape), so as to achieve the customization of the drug release curve of the oral film, and prepare the oral film with a customizable drug release curve.

[0062] In the corresponding formula (I), n=3, h1=0 mm, h2=0.2 mm, h3=0.1 mm, k1=1320.47 min / mm, k2=75.94 min / mm.

[0063] like Figure 5 As shown in D in the figure, the in vitro drug dissolution experiment proves that the oral film can release the drug for the first time after taking it, release the drug for the second time after 4 hours, and release the drug for the third time after 8 hours. The oral film can prepare the nifedipine drug taken three times a day to release three times in one time, thereby reducing the number of times the drug is taken and improving patient compliance.

[0064] The embodiments described above provide a detailed description of the technical solutions of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, supplements or similar substitutions made within the scope of the principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing an oral film with a customizable drug release profile, characterized in that: The following steps are involved: (1) preparing a double-layer drug film including a barrier layer and a drug sustained-release layer, wherein the barrier layer is a metal film capable of reacting with an acidic solution, the drug sustained-release layer includes a water-soluble small molecule drug and a sustained-release polymer, and the drug sustained-release layer is edge-sealed and fixed on the barrier layer; (2) folding the double-layer drug film to obtain an oral film with an origami structure, thereby achieving customization of the drug release curve of the oral film, and preparing the oral film with a customizable drug release curve; In the in vitro model, the tailored drug release profile was expressed as: In formula (I), c t represents the drug concentration released at time t, n represents the number of pulses of drug release, M i represents the amount of drug in the i-th layer, g i (t)=1+ where h i and h j They represent the thickness of the barrier layer before drug release in the i-th and j-th layers, respectively, and k1 and k2 are fitting parameters for specific barrier layers; The metal film can react with gastric juice and is selected from magnesium film, magnesium-aluminum alloy film, magnesium-lithium alloy film or zinc film; the thickness of the metal film does not exceed 200 microns; The sustained-release polymer is selected from polycaprolactone, polyvinyl alcohol, polylactic acid, pectin, polylactic acid-glycolic acid copolymer, chitosan, polyvinyl pyrrolidone or hydroxypropyl methylcellulose.

2. The method for preparing an oral film with a customizable drug release profile according to claim 1, characterized in that: The thickness of the metal film is 50-200 microns.

3. The method for preparing an oral film with a customizable drug release profile according to claim 1, characterized in that: The water-soluble small molecule drugs include doxofylline, hydrocortisone, metformin, nifedipine, caffeine, doxazosin, amiloride or clonidine.

4. The method for preparing an oral film with a customizable drug release profile according to claim 1, characterized in that: In the drug sustained-release layer, the mass ratio of water-soluble small molecule drugs to sustained-release polymers is 1:5-100.

5. The method for preparing an oral film with a customizable drug release profile according to claim 1, characterized in that: The drug sustained-release layer is edge-sealed and fixed on the barrier layer by using a biosafety material, and the biosafety material is a cellulose-based double-sided tape.

6. The method for preparing an oral film with a customizable drug release profile according to claim 1, characterized in that: During the folding process, multiple double-layered origami structures are formed.

7. An oral film prepared according to the method for preparing an oral film with a customizable drug release profile according to any one of claims 1 to 6.

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