CN113908132A - Agomelatine and derivative oral patch preparation thereof and preparation method thereof - Google Patents

Abstract

The invention discloses an agomelatine and a derivative oral patch preparation thereof and a preparation method thereof, wherein the agomelatine and the derivative oral patch preparation are absorbed through oral mucosa, so that the bioavailability of the agomelatine is improved. The preparation has certain porosity and hardness through a vacuum freeze-drying molding method, can be better adhered to oral mucosa for drug release, and simultaneously, a high polymer material and an active substance are added in the preparation process to form inclusion, so that the active ingredient can be slowly released, a certain concentration of agomelatine in a human body at night is maintained, and the effects of improving sleep and resisting depression are remarkable.

Description

Agomelatine and derivative oral patch preparation thereof and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an agomelatine and agomelatine derivative oral patch preparation and a preparation method thereof.

Background

Agomelatine is a drug for treating adult depression, the original company of which is Schveya, France, the specification of which is 25mg, and the dosage form of which is a tablet. The medicine is marketed in European Union in 2009 and imported into China in 2011. The usage and dosage of the medicine are as follows: the recommended dose is 25mg once daily, taken before sleep, and if the symptoms do not improve after two weeks of treatment, the dose can be increased to 50mg once daily, i.e. 25mg per two tablets, taken before sleep.

The oral administration of the drug is fast and good in absorption (more than 80%), but very small in bioavailability (less than 5%), because agomelatine has a significant first pass effect in the liver.

The original research company, executed viuya and nova in 2011 to develop agomelatine sublingual tablets, completed phase I and phase II clinics, but failed in all three phase III clinics, and the original research company, mentioned in domestic patent CN1981752A, proposed that a coated solid agomelatine-dispersible pharmaceutical composition administered by oral, oromucosal or sublingual route, limited the first pass effect of the liver, increased bioavailability of the active ingredient and reduced inter-individual variation compared to conventional agomelatine pharmaceutical compositions for enteral administration.

The original research patent avoids the first pass effect of the liver, improves the bioavailability of active ingredients and reduces the difference among individuals by preparing the agomelatine into sublingual tablets and absorbing and administering the agomelatine through oral mucosa. At present, the clinical failure of manufacturers in stage III is probably because the sublingual tablets still can move in the oral cavity, the sublingual tablets have poor control in the process of large-scale clinical tests, and the situation that the swallowing of the tablets and part of active ingredients enter the gastrointestinal tract along with saliva is difficult to avoid due to different medication education degrees of patients, which can cause the failure of the clinical tests.

Through the patent analysis of the agomelatine preparation, the original patent is mainly designed to be rapidly disintegrated in the oral cavity and absorbed through sublingual or oral mucosa, so that the first-pass effect of conventional oral administration is avoided, the bioavailability is improved, and the inter-individual difference is reduced. Chinese patent CN1287780C also solves the tingling of API to oral mucosa, making the patient more compliant. According to the research of Chinese patent CN102949360A, the relative bioavailability of the tablet absorbed by the buccal mucosa is improved by 1.5 to 1.8 times compared with the common oral dispersible tablet. Moreover, sublingual tablets, orally disintegrating tablets and orally dispersible tablets cannot avoid the gastrointestinal first-pass effect of active ingredients.

At present, related preparation researches are arranged around the directions of obvious agomelatine first-pass effect, low bioavailability, large individual difference, poor patient compliance (oral cavity tingling feeling) and the like. The preparation mainly relates to the dosage forms of solid sustained-release preparations (sustained-release tablets and sustained-release capsules), transdermal patches, dispersible tablets, sublingual tablets, orally disintegrating tablets, freeze-dried orally disintegrating tablets, liposome tablets, oral liquid, effervescent dry suspension and sustained-release microspheres for long-acting injection.

The solid sustained-release capsule disclosed in chinese patent CN105194514A is still administered orally and absorbed through gastrointestinal tract, and high first-pass effect cannot be avoided. The transdermal patch is absorbed by percutaneous slow release, so that the first-pass effect can be avoided, but the agomelatine is a melatonin receptor agonist, if existing in vivo for a long time in the daytime, the agomelatine can cause lethargy of people, so that adverse reactions are not acceptable, and the long-acting liposome and the long-acting microsphere injection also have the problems.

In summary, there is currently no agomelatine oral patch, but such a dosage form has significant clinical advantages and needs.

Disclosure of Invention

In view of the problems in the prior art, the invention aims to provide an agomelatine and agomelatine derivative oral patch preparation and a preparation method thereof, and provides an agomelatine oral patch with obvious clinical advantages and requirements.

In order to achieve the purpose, the invention is realized by the following technical scheme:

an oral patch preparation of agomelatine and derivatives thereof, comprising: a drug-containing layer and a back lining coating layer; the medicine-containing layer comprises active ingredients, skeleton supporting agent, adhesive, suspending agent, penetration enhancer and correctant; the back lining coating layer contains coating material and medicinal dye.

Preferably, the matrix support agent is one or more selected from lactose, mannitol, glycine, serine, and microcrystalline cellulose. The matrix support is preferably mannitol.

Preferably, the binder is one or more selected from pullulan, hydroxypropyl methylcellulose, polyethylene oxide and hydroxyethyl cellulose. The binder is preferably a combination of pullulan and hydroxypropyl methylcellulose.

Preferably, the suspending agent is one or more selected from guar gum, gelatin, xanthan gum and konjac gum. Guar gum is preferred.

Preferably, the penetration enhancer is one or more selected from oleic acid, poloxamer and polysorbate. Polysorbitol is preferred.

Preferably, the flavoring agent is one or more selected from stevioside, sucrose, saccharin sodium and aspartame. Preferably stevioside.

Preferably, the coating material is ethyl cellulose.

Preferably, the medicinal dye is sunset yellow.

Preferably, the weight percentage of the raw materials is as follows:

the active ingredient is agomelatine, and the content of the agomelatine is 1.1% -5.6%;

the skeleton supporting agent is mannitol, and the content of the mannitol is 20% -70%;

the adhesive comprises a pullulan and hydroxypropyl methyl cellulose composition, wherein the content of hydroxypropyl methyl cellulose is 12-30%, and the content of pullulan is 12-30%;

the suspending agent is guar gum, and the content of the suspending agent is 0.4 to 1.2 percent;

the penetration enhancer is polysorbate, and the content of the penetration enhancer is 1.2% -2.5%;

the flavoring agent is stevioside, and the content of the stevioside is 1.0 to 3.5 percent;

the coating material is ethyl cellulose, and the content of the ethyl cellulose is 2% -10%;

the medicinal dye is sunset yellow, and the content is 0.02% -0.05%.

Further, the weight percentage of the raw materials is as follows:

2.2% of agomelatine;

41.4% of mannitol;

25.4% of hydroxypropyl methyl cellulose;

21.2% of pullulan;

0.8% of guar gum;

1.8% of polysorbate;

2.2% of stevioside;

5% of ethyl cellulose;

sunset yellow 0.03%.

The invention also provides a preparation method of the agomelatine and the agomelatine derivative oral patch preparation, which comprises the following specific steps:

(1) crushing the agomelatine raw material medicine, wherein D90 is 5-30 mu m;

(2) placing hydroxypropyl methylcellulose and guar gum into an emulsification tank, fully swelling in advance, adding agomelatine, mannitol, pullulan, polysorbate and stevioside into the solution, and starting a stirring and shearing device to obtain a uniform suspension solution;

(3) degassing the solution;

(4) injecting the degassed solution into a mold, putting the mold into a freeze dryer, and pre-freezing for 15-60 min at the temperature of-50 ℃ to-10 ℃;

(5) preparing coating liquid from ethyl cellulose and medicinal dye;

(6) removing the pre-frozen molded product from the mold, and uniformly spraying the coating liquid to the curved surface of the pre-frozen molded product;

(7) and freeze-drying for 2-8h under the pressure of 0.1-12 mbar and the temperature of-30-40 ℃ to obtain the product.

The freeze-dried tablet has a loose porous structure, can be well adhered to oral mucosa when meeting oral mucus, is slowly dissolved and released in the oral mucus, is directly absorbed into blood through the mucosa, prevents the drug from generating a first-pass effect when passing through gastrointestinal tracts, and improves the bioavailability; the coating of the hydrophobic material on the back of the tablet also well prevents the active ingredients from entering the gastrointestinal tract through saliva, further ensures that the active ingredients can only be absorbed into blood through oral mucosa, and simultaneously increases the convenience of patients in the use process; some natural or organic polymer materials added in the prescription can wrap the active ingredients to play a role of slow release, so that the active ingredients are ensured to be continuously released within a certain time after the medicine is taken, and meanwhile, the tingling feeling of the active ingredients in the oral cavity is reduced.

The beneficial effects of the invention compared with the prior art comprise:

the invention fixes the oral patch at a certain place of the oral cavity, ensures that the active ingredients are absorbed through the oral mucosa, and effectively avoids the first pass effect of the liver. The resulting oral patch, which dissolves slowly in saliva, allows the patch to dissipate only over time without having to remove the patch from the oral cavity. Effectively adhere to the wet surfaces in the mouth and are particularly soft, which provides comfort to the sensitive mouth. The user can stick the oral patch to the gums, cheeks, lips, or tongue without first drying the saliva from the tissue. When the patient presses it in the desired position for 10 to 30 seconds, the patch sticks to the place where it is in contact without moving, which is very advantageous for drugs whose first-pass effect is significant and needs to be absorbed through the oral mucosa.

In addition, the invention uses a vacuum freeze drying technology, so that the tablet has certain porosity and hardness, can be better adhered to oral mucosa for drug release, and simultaneously, a high polymer material and an active substance are added in the vacuum drying process to form inclusion, so that the active ingredient can be slowly released. In vitro release studies show that the agomelatine can be slowly released within 3 hours, so that even if the half-life period of the agomelatine in a human body is only 1-2 hours, a certain concentration of the agomelatine in the human body at night can be maintained, and the agomelatine sustained-release tablet is very helpful for improving sleep and resisting depression.

Drawings

FIG. 1 is a side view of an oral patch formulation of the present invention;

FIG. 2 is a top view of an oral patch formulation of the present invention;

FIG. 3 is a graph showing in vitro release rate results of examples 1 to 3 of the present invention.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.

Example 1:

see table 1, recipe for 10000 tablets:

table 1 prescription 1 raw material ratio

	Amount of prescription	Percentage of
			Agomelatine	19.8g	2.2％
Mannitol	372.6g	41.4％
			Pullulan	190.8g	21.2％
Hydroxypropyl methylcellulose	228.6g	25.4％
			Guar gum	7.2g	0.8％
Oleic acid	16.2g	1.8％
			Stevioside	19.8g	2.2％
Ethyl cellulose	45g	5％
			Sunset yellow	0.27g	0.03％

The preparation method comprises the following steps:

a. crushing the agomelatine raw material medicine, wherein D90 is about 15 mu m;

b. putting hydroxypropyl methylcellulose and guar gum into an emulsification tank, fully swelling in advance, adding agomelatine, mannitol, pullulan, polysorbate and stevioside into the solution, and starting a stirring and shearing device to obtain a uniform suspension solution;

c. degassing the solution;

d. injecting the degassed solution into a mold, placing into a freeze dryer, and pre-freezing at-30 deg.C for 35 min;

e. preparing coating liquid from ethyl cellulose and medicinal dye;

f. removing the pre-frozen molded product from the mold, and uniformly spraying the coating liquid to the curved surface of the pre-frozen molded product;

g. freeze drying for 5h under the pressure of 0.1 mbar-12 mbar and the temperature of 10 ℃ to obtain the product.

The above oral patch preparation has a shape shown in fig. 1-2, wherein one side of the plane (lower side in fig. 1) is attached to one side of the oral cavity, and one side of the curved surface (upper side in fig. 1) is coated to prevent the active ingredient from leaking.

Example 2:

see table 2, recipe for 10000 tablets:

table 2 prescription 2 raw material ratio

	Amount of prescription	Percentage of
			Agomelatine	19.8g	2.2％
Mannitol	417.6g	46.4％
			Pullulan	168.3g	18.7％
Hydroxypropyl methylcellulose	206.1g	22.9％
			Guar gum	7.2g	0.8％
Oleic acid	16.2g	1.8％
			Stevioside	19.8g	2.2％
Ethyl cellulose	45g	5％
			Sunset yellow	0.27g	0.03％

The preparation method comprises the following steps:

a. crushing the agomelatine raw material medicine, wherein D90 is about 5 mu m;

b. putting hydroxypropyl methylcellulose and guar gum into an emulsification tank, fully swelling in advance, adding agomelatine, mannitol, pullulan, polysorbate and stevioside into the solution, and starting a stirring and shearing device to obtain a uniform suspension solution;

c. degassing the solution;

d. injecting the degassed solution into a mold, placing into a freeze dryer, and pre-freezing at-50 deg.C for 15 min;

e. preparing coating liquid from ethyl cellulose and medicinal dye;

f. removing the pre-frozen molded product from the mold, and uniformly spraying the coating liquid to the curved surface of the pre-frozen molded product;

g. freeze drying for 8h under the pressure of 0.1 mbar-12 mbar and the temperature of-30 ℃ to obtain the product.

The above oral patch preparation has a shape shown in fig. 1-2, wherein one side of the plane (lower side in fig. 1) is attached to one side of the oral cavity, and one side of the curved surface (upper side in fig. 1) is coated to prevent the active ingredient from leaking.

Example 3:

see table 3, recipe for 10000 tablets:

table 3 prescription 3 raw material ratio

	Amount of prescription	Percentage of
			Agomelatine	19.8g	2.2％
Mannitol	327.6g	36.4％
			Pullulan	213.3g	23.7％
Hydroxypropyl methylcellulose	251.1g	27.9％
			Guar gum	7.2g	0.8％
Oleic acid	16.2g	1.8％
			Stevioside	19.8g	2.2％
Ethyl cellulose	45g	5％
			Sunset yellow	0.27g	0.03％

The preparation method comprises the following steps:

a. crushing the agomelatine raw material medicine, wherein D90 is about 30 mu m;

b. putting hydroxypropyl methylcellulose and guar gum into an emulsification tank, fully swelling in advance, adding agomelatine, mannitol, pullulan, polysorbate and stevioside into the solution, and starting a stirring and shearing device to obtain a uniform suspension solution;

c. degassing the solution;

d. injecting the degassed solution into a mold, placing into a freeze dryer, and pre-freezing at-10 deg.C for 60 min;

e. preparing coating liquid from ethyl cellulose and medicinal dye;

f. removing the pre-frozen molded product from the mold, and uniformly spraying the coating liquid to the curved surface of the pre-frozen molded product;

g. freeze drying for 2h under the pressure of 0.1 mbar-12 mbar and the temperature of 40 ℃ to obtain the product.

The above oral patch preparation has a shape shown in fig. 1-2, wherein one side of the plane (lower side in fig. 1) is attached to one side of the oral cavity, and one side of the curved surface (upper side in fig. 1) is coated to prevent the active ingredient from leaking.

The following are the quality control requirements:

1. appearance of the product

The product is a double-layer tablet, with white layer as medicine-containing layer and yellow layer as protective layer. The oral patch should be complete, smooth and uniform in color.

2. Content uniformity

10 test samples are taken and respectively placed in 50ml measuring bottles, a proper amount of 80% methanol solution is added, the mixture is sufficiently shaken to dissolve the agomelatine, and is diluted to a scale, shaken up, filtered and analyzed by HPLC. The results should meet pharmacopoeia requirements.

3. Content (wt.)

20 test samples are taken and ground, a proper amount of fine powder (about 5mg of agomelatine) is taken and placed in a 100ml measuring flask, 80% methanol solution is added for dissolution and dilution to the scale, shaking is carried out, and HPLC analysis is carried out after filtration.

4. Degree of in vitro Release

According to the first method of 0931, four parts of the pharmacopoeia 2020, China, the dissolution medium is phosphate buffer solution with pH6.8, the temperature is 37 ℃, the rotation speed is 50rpm, samples are taken at intervals of 4 hours, and HPLC analysis is performed.

5. Limit of microorganism

Unless otherwise specified, the microbial limit of the sterile product was checked: the microbial count (general rule 1105), the controlled bacteria test (general rule 1106) and the non-sterile drug microbial limit criteria (general rule 1107) should be in compliance with the regulations.

TABLE 4 test results

	Prescription 1	Prescription 2	Prescription 3
				Appearance of the product	Meets the requirements	Meets the requirements	Meets the requirements
Content uniformity	Meets the requirements	Meets the requirements	Meets the requirements
				Content (wt.)	98.6％	99.0％	98.8％

Referring to table 4, the oral patch preparations of formulas 1 to 3 prepared by the present invention all meet the requirements in terms of appearance, content uniformity, etc., and the content is above 98%. In addition, referring to fig. 3, the results of in vitro release degrees measured for the oral patch preparations of formulas 1 to 3 show that the three formulations of formulas all achieve maximum release within about 3 hours, and can satisfy the requirement that the active ingredient exists in the human body for a certain time and at a certain concentration at night.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (10)

1. An oral patch preparation of agomelatine and a derivative thereof is characterized by comprising: a drug-containing layer and a back lining coating layer; the medicine-containing layer comprises active ingredients, skeleton supporting agent, adhesive, suspending agent, penetration enhancer and correctant; the back lining coating layer contains coating material and medicinal dye.

2. The oral patch preparation of agomelatine and its derivatives according to claim 1, wherein the matrix support is one or more selected from lactose, mannitol, glycine, serine, microcrystalline cellulose.

3. The oral patch preparation of agomelatine and its derivatives according to claim 1, wherein the binder is one or more selected from pullulan, hydroxypropylmethyl cellulose, polyethylene oxide, hydroxyethyl cellulose.

4. The oral patch preparation of agomelatine and its derivatives according to claim 1, wherein the suspending agent is one or more selected from guar gum, gelatin, xanthan gum, konjac gum.

5. The oral patch formulation of agomelatine and its derivatives according to claim 1, wherein the penetration enhancer is one or more selected from the group consisting of oleic acid, poloxamers, and polysorbates. Polysorbitol is preferred.

6. The oral patch preparation of agomelatine and its derivatives according to claim 1, wherein the flavoring agent is one or more selected from stevioside, sucrose, saccharin sodium, aspartame.

7. The oral patch formulation of agomelatine and its derivatives according to claim 1, wherein the coating material is ethyl cellulose; the medicinal dye is sunset yellow.

8. The oral patch preparation of agomelatine and its derivatives according to any one of claims 1 to 7, wherein the raw materials in weight percentage are:

the active ingredient is agomelatine, and the content of the agomelatine is 1.1% -5.6%;

the skeleton supporting agent is mannitol, and the content of the mannitol is 20% -70%;

the adhesive comprises a pullulan and hydroxypropyl methyl cellulose composition, wherein the content of hydroxypropyl methyl cellulose is 12-30%, and the content of pullulan is 12-30%;

the suspending agent is guar gum, and the content of the suspending agent is 0.4 to 1.2 percent;

the penetration enhancer is polysorbate, and the content of the penetration enhancer is 1.2% -2.5%;

the flavoring agent is stevioside, and the content of the stevioside is 1.0 to 3.5 percent;

the coating material is ethyl cellulose, and the content of the ethyl cellulose is 2% -10%;

the medicinal dye is sunset yellow, and the content is 0.02% -0.05%.

9. The oral patch preparation of agomelatine and its derivatives according to claim 8, wherein the raw materials comprise, by weight:

2.2% of agomelatine;

41.4% of mannitol;

25.4% of hydroxypropyl methyl cellulose;

21.2% of pullulan;

0.8% of guar gum;

1.8% of polysorbate;

2.2% of stevioside;

5% of ethyl cellulose;

sunset yellow 0.03%.

10. A preparation method of an agomelatine and agomelatine derivative oral patch preparation is characterized by comprising the following specific steps:

(1) crushing the agomelatine raw material medicine, wherein D90 is 5-30 mu m;

(2) placing hydroxypropyl methylcellulose and guar gum into an emulsification tank, fully swelling in advance, adding agomelatine, mannitol, pullulan, polysorbate and stevioside into the solution, and starting a stirring and shearing device to obtain a uniform suspension solution;

(3) degassing the solution;

(4) injecting the degassed solution into a mold, putting the mold into a freeze dryer, and pre-freezing for 15-60 min at the temperature of-50 ℃ to-10 ℃;

(5) preparing coating liquid from ethyl cellulose and medicinal dye;

(6) removing the pre-frozen molded product from the mold, and uniformly spraying the coating liquid to the curved surface of the pre-frozen molded product;

(7) and freeze-drying for 2-8h under the pressure of 0.1-12 mbar and the temperature of-30-40 ℃ to obtain the product.

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