JP2017001955A - Method for producing orally administered film formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally administered film formulation that causes no scrap and has excellent coating accuracy and a method for producing the same.SOLUTION: A method for producing an orally administered film formulation is characterized by forming a medicine-containing layer by screen printing of a medicine-containing liquid with a thixotropy index of 0.1 or more and 0.7 or less.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a film preparation for oral administration using a screen printing technique and a film preparation for oral administration.

  In recent years, film preparations have been studied and marketed as preparations for oral administration in which drugs can be transmucosally administered from the oral mucosa, or orally without water, in addition to preparations such as tablets, granules and capsules. (For example, Patent Documents 1 to 3).

  As a manufacturing technique of these film preparations, a method of punching / cutting a sheet obtained by a method of repeatedly laminating coating and drying (Patent Document 4) or a method of pasting coated and dried materials (Patent Document 5) It has been known. In any method, the coater method is used for coating. Further, as a method other than the coating method by the coater method, a method of applying nicotine to the surface of a previously formed water-soluble film by an ink jet printing technique has been reported (Patent Document 6).

Special table 2009-544619 Special table 2012-522742 gazette International Publication No. 2010/023874 JP 09-235220 A JP 2004-196784 A JP 2012-170889 A

  However, in the method of coating by the coater method, a step of punching / cutting a sheet obtained by laminating or bonding after coating drying is necessary, and the remainder after punching / cutting, so-called scrap is generated. Therefore, there is a problem that drug loss increases. This problem is serious when the drug is expensive and when the drug is restricted in handling and disposal as specified by the drug. In addition, a high-viscosity preparation liquid with a high solid content cannot be applied by application using an inkjet printing technique. Moreover, if the viscosity of a preparation liquid is made low, the usage-amount of a solvent will increase and it will be necessary to apply | coat repeatedly and is inefficient. Furthermore, there is a problem of clogging when a preparation liquid in which a drug or excipient is dispersed in powder is applied.

  In addition, pharmaceuticals are required to have high content uniformity. For example, in order to meet the Japanese Pharmacopoeia (16) formulation uniformity test, the coating accuracy is 4.7 as a relative standard deviation of the coating amount. % Or less.

  Accordingly, an object of the present invention is to provide a film preparation for oral administration having no coating scrap and good coating accuracy, and a method for producing the same.

  Therefore, the present inventor studied paying attention to the screen printing technique, and found that the application of the drug layer by the technique can prevent the generation of scrap like coating by the coater method. However, when the drug-containing liquid was formed by screen printing, it was found that the variation in the coating amount was large and it was difficult to adapt it to the formulation uniformity test of the Japanese Pharmacopoeia. Therefore, as a result of further investigation, it is necessary to meet the Japanese Pharmacopoeia formulation uniformity test by changing the coating accuracy depending on the thixotropy of the drug-containing liquid applied by screen printing and keeping the thixotropy index within a certain range. And found that the relative standard deviation of the coating amount can be controlled to 4.7% or less, and completed the present invention.

  That is, the present invention provides the following [1] to [6].

[1] A method for producing a film preparation for oral administration, wherein the drug-containing layer is formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 to 0.7.
[2] The method for producing a film preparation for oral administration according to [1], wherein the thixotropic index of the drug-containing liquid is 0.15 or more and 0.6 or less.
[3] The method for producing a film preparation for oral administration according to [1] or [2], wherein the drug-containing layer has functional layers on both sides or one side.
[4] The method for producing a film preparation for oral administration according to [3], wherein the functional layer is a layer containing a water-soluble polymer.
[5] The method for producing a film preparation for oral administration according to any one of [1] to [4], wherein the drug-containing liquid is a liquid containing a water-soluble polymer, a drug, and a thixotropic substance.
[6] A film preparation for oral administration obtained by the production method according to any one of [1] to [5].

  According to the production method of the present invention, a film preparation for oral administration that produces almost no scrap due to the punching / cutting process and has a small weight variation in coating amount required as a pharmaceutical product is industrially advantageously obtained.

The example of the pattern of a screen printing plate is shown.

  The method for producing a film preparation for oral administration of the present invention is characterized in that the drug-containing layer is formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 or more and 0.7 or less.

  In the present invention, the drug-containing liquid used for screen printing maintains a relative standard deviation of 4.7% or less so that the coating accuracy can be adapted to the formulation uniformity test of the Japanese Pharmacopoeia. .7 or less is important. If the thixotropy index is less than 0.1, application is not possible or the relative standard deviation exceeds 4.7%. On the other hand, if the thixotropy index exceeds 0.7, the additive for imparting thixotropy aggregates in the drying step, and a uniform preparation cannot be obtained. A preferable thixotropy index is 0.15 or more, more preferably 0.17 or more. Moreover, a preferable thixotropy index is 0.65 or less, more preferably 0.6 or less. The range of a preferable thixotropy index is 0.15-0.65, More preferably, it is 0.17-0.6.

  Here, the thixotropy index (TI) is a value calculated from the viscosity of the liquid at 5 rpm and 50 rpm using the following equation (1), and is a value indicating thixotropy performance.

TI = Log (η ₅ / η ₅₀ ) / Log (50/5) (1)
η ₅ : Viscosity at ₅ rpm η ₅₀ : Viscosity at ₅₀ rpm

  The viscosity of the drug-containing liquid is preferably 20000 mPa · s or more at 5 rpm, more preferably 20000 to 40000 mPa · s. The viscosity at 50 rpm is preferably 10,000 to 30,000 mPa · s, more preferably 12,000 to 20,000 mPa · s. The viscosity at 100 rpm is preferably 8000 to 20000 mPa · s, and more preferably 10,000 to 15000 mPa · s.

  The drug-containing layer formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 or more and 0.7 or less is a layer containing, for example, a water-soluble polymer, a drug, and a thixotropy-imparting substance. Here, the water-soluble polymer is not particularly limited as long as it has film-forming properties and is edible. For example, hypromellose (hydroxypropylmethylcellulose), hydroxypropylcellulose, pullulan, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose Examples include calcium, carboxymethylcellulose potassium, carboxymethylcellulose, polyvinylpyrrolidone, and sodium alginate. These water-soluble polymers can be used alone or in combination of two or more.

  The drug is not particularly limited as long as it is an orally administrable drug, and includes active ingredients such as pharmaceuticals, functional foods, foods for specified health use. Drugs include central nervous system drugs (hypnotic sedatives, anxiolytics, antiepileptics, antipyretic analgesics, antistimulants, stimulants, antiparkinsonian agents, psychiatric agents, general cold agents, etc.), peripheral nerves Systemic drugs (local anesthetics, skeletal muscle relaxants, autonomic nerve agents, antispasmodics, etc.), sensory organ drugs (ophthalmic drugs, antipruritics, etc.), cardiovascular drugs (cardiotonic drugs, arrhythmic drugs, diuretics) , Antihypertensive, vasoconstrictor, vasodilator, hyperlipidemia, etc.), respiratory organs (respiratory, antitussive, expectorant, bronchodilator, gargle etc.), digestive organ Drugs (depressants, intestinal preparations, peptic ulcers, laxatives, enemas, etc.), hormones (salivary gland hormones, thyroid / parathyroid hormones, anabolic steroids, adrenal hormones, follicular hormones and luteinizing hormones, Mixed hormones), genitourinary and anal drugs ( Miya Shrink Agents, Contraceptives, Vaginal Agents, Dental Oral Drugs (Dental Antibiotics, etc.), Vitamins, Nutrition Tonics (Inorganic Preparations, etc.), Blood and Body Fluids (Blood Coagulation Inhibitors, etc.) , Liver disease agent, antidote, gout treatment agent, diabetes agent, cell stimulant, tumor agent (alkylating agent, antimetabolite, etc.), allergy agent (antihistamine, etc.), herbal medicine, Chinese medicine, antibiotics Examples include substance preparations, antiviral agents, anthelmintics, alkaloid narcotics (opium alkaloids, coca alkaloids, etc.), non-alkaloid narcotics (synthetic narcotics such as fentanyl citrate), and the like.

Examples of the thixotropic substance include light anhydrous silicic acid, kaolin, starch (starch), cross-linked polyvinyl pyrrolidone (Kollidon CL), low-substituted hydroxypropyl cellulose, and the like.
These substances imparting thixotropy can be adjusted for thixotropy by adjusting the particle size in addition to the addition amount.
Furthermore, thixotropic property can be imparted by adding a polymer compound that forms a gel having low fluidity when dissolved, such as sodium carboxymethylcellulose or carboxyvinyl polymer.

In addition to the above-described components, the drug-containing layer can contain plasticizers, sugars, stabilizers, sweeteners, pH adjusters, colorants, flavoring agents, and the like.
As the plasticizer, for example, propylene glycol, glycerin, polyethylene glycol (macrogol), sesame oil, castor oil, triethyl citrate, sucrose fatty acid ester and the like can be used.
Examples of the saccharide include sucrose, fructose, glucose, maltose (maltose), sucrose, sugar alcohol (such as maltitol, reduced maltose starch syrup, sorbitol, erythritol, xylitol), trehalose, and the like.
As the stabilizer, ascorbic acid, sodium hydrogen sulfite, sodium sulfite, sodium edetate, erythorbic acid, tocopherol acetate, dibutylhydroxytoluene, butylhydroxyanisole and the like can be used.
As the sweetener, aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin and the like can be used. As the pH adjuster, tartaric acid, citric acid, phosphoric acid and the like and pharmaceutically acceptable salts thereof can be used. As the colorant, iron sesquioxide, yellow iron sesquioxide, copper chlorophyllin sodium, food coloring, and the like can be used. Flavors such as menthol and vanilla, orange, strawberry grapefruit can be used as a flavoring agent.

  Since the solvent of the drug-containing liquid is for oral administration, water, ethanol or a mixed solvent thereof is preferable.

  The screen printing apparatus and conditions used for forming the drug-containing layer are not particularly limited as long as the drug-containing layer can be formed in a desired shape.

  As a material for the printing (coating) screen, natural fiber screens such as silk and cotton, synthetic resin screens such as polyester and nylon, and metal screens such as stainless and tungsten can be used. Of these, metal screens, particularly stainless steel screens are preferred from the standpoint of ensuring printing position accuracy and the amount of drug-containing liquid applied.

  The wire diameter and the number of meshes of the screen mesh can be appropriately selected and combined depending on the target coating amount and the fluid characteristics of the drug-containing liquid. When a drug-containing liquid is intended for application, if a low mesh having a large wire diameter is used, a high application amount can be obtained, but the uniformity and smoothness of the application surface may be deteriorated. On the other hand, when a high mesh with a thin wire diameter is used, the amount of application decreases, and when the drug in the drug-containing liquid is dispersed in powder, it may cause clogging. For these reasons, it is preferable that the screen mesh has a line diameter of 0.010 to 0.160 mm and the number of meshes is 40 to 730.

  Examples of screen weaving methods include plain weave, twill weave, plain tatami weave, and twill woven weave. However, plain weave or twill weave is preferred from the standpoint of printability and cleanability.

Of the printing (coating) conditions, the squeegee speed is preferably 10 mm / second to 300 mm / second, and is suitably adjusted according to the viscosity and thixotropy of the drug-containing liquid. Among these, 50 mm / sec or more is preferable from the viewpoint of transferability of drug-containing liquid and productivity.
The squeegee pressure is such that the squeegee is pushed in by about 0.5 mm to 3.0 mm, and is suitably adjusted according to the target application amount, the viscosity of the drug-containing liquid and the thixotropy. Of these, a squeegee pressure at which the squeegee is pushed by about 0.5 mm to 1.0 mm is preferable from the viewpoint of printing position accuracy.

  Drying after screen printing is preferably warm air spraying, far-infrared rays, heating drying with a microwave or vacuum drying, and a hot air spraying method is more preferable. The temperature of the warm air is preferably 100 ° C. or less, and more preferably 40 to 70 ° C.

  The film preparation for oral administration of the present invention may be the drug-containing layer alone, but may be provided with functional layers on both sides or one side of the drug-containing layer. The functional layer can have various functions such as making the formulation easy to handle, masking the bitter taste of the drug, protecting the drug layer from moisture, oxygen, light, etc., and stabilizing the drug in the drug layer. . The functional layer can contain all components excluding the drug from the components contained in the drug-containing layer. Further, when the functional layer is formed by screen printing, a thixotropic property-imparting substance may be contained, and when the functional layer is applied by a roll coater, it is not necessary to add a thixotropic property-imparting substance. When the functional layer is formed by screen printing, the thixotropy index and viscosity of the functional layer preparation liquid are preferably the same as those of the drug-containing liquid.

For example, production of a film agent having a three-layer structure of (functional layer) / (drug-containing layer) / (functional layer) can be performed by the following method.
(1) A functional layer preparation solution is applied and dried on a polyester film using a screen printing technique to form a functional layer, and then a drug-containing layer and a functional layer are similarly applied and dried using a screen printing technique in that order. Can be produced repeatedly.
(2) A functional layer preparation solution was applied and dried on a polyester film using a roll coater to produce a functional layer, and then a drug-containing solution was applied and dried thereon using a screen printing technique to produce a drug-containing layer. Thereafter, the functional layer preparation liquid is further applied and dried from above using a roll coater. Furthermore, it is possible to punch and manufacture the part where the drug-containing layer is formed.
(3) A functional layer preparation liquid is applied and dried on a polyester film using a roll coater to produce a functional layer, and then a drug-containing liquid is applied thereon using a screen printing technique to produce a drug-containing layer. Next, after bonding so that the drug-containing layers are in contact with each other, the drug-containing layer portion can be punched and manufactured.
The functional layers provided on each surface of the drug-containing layer may have the same composition or different compositions. Moreover, it can also manufacture combining the method of (1)-(3).

  EXAMPLES Next, an Example is given and this invention is demonstrated in detail.

(1) Preparation of functional layer preparation solution Reduced maltose starch syrup (10 parts by mass), polyethylene glycol 400 (PEG-400) (8 parts by mass) and edible yellow pigment (0.125 parts by mass) in purified water (appropriate amount) did. To this solution, a solution in which titanium oxide (10 parts by mass) is dispersed in ethanol (appropriate amount) is added, and after dispersion, hydroxypropylmethylcellulose (HPMC) (72 parts by mass) is added and stirred to dissolve to prepare a functional layer preparation solution It was.

(2) Preparation of drug-containing solution Reduced maltose starch syrup (maltitol), sucralose and polyethylene glycol 400 (PEG-400) were added to purified water and dissolved by stirring. Hydroxypropyl cellulose (HPC) and light anhydrous silicic acid were stirred into a solution in which flurbiprofen was added and dispersed in this solution, and stirred until uniform.
The composition of each preparation solution is as shown in the table below.

(3) Measurement of viscosity of prepared solution Using a Brookfield viscometer, the viscosity at 5 rpm and 50 rpm was measured according to the Japanese Pharmacopoeia viscosity measurement method.
(4) Calculation of thixotropy index (TI) It calculated from the viscosity of 5 rpm and 50 rpm of a preparation liquid using said Formula (1).

(5) Screen printing plate A screen mesh is mounted on a 320 mm x 320 mm frame, and a coating of 12 mm x 18 mm and r = 1.8 mm can be applied in 30 places (6 x 5) in a matrix. A screen printing plate was used (FIG. 1).
The main specifications of the screen printing version are as shown in the table below.

(6) Preparation of film agent Application drying of functional layer preparation liquid Using a roll coater, the functional layer preparation liquid is applied to a polyester film having a thickness of 75 μm so that the coating amount after drying is 18.4 g / m ^2. The coating was dried.
What coated and dried the functional layer on the polyester film was made into the coating object.
Coating / Drying of Drug-Containing Liquid In a screen printer, an article to be coated was set so that the drug-containing layer could be coated on the functional layer. Further, the clearance between the screen printing plate and the coated object was adjusted to 1.8 mm. An appropriate amount of the preparation liquid was applied onto the screen printing plate, and the flat squeegee was moved to perform application.
What applied the preparation liquid was put into the drier and dried. Next, the coated and dried product-coated layer-coated portions were punched one by one, and the polyester film was peeled off to obtain a two-layer film agent composed of (functional layer) / (drug-containing layer).
The coating and drying conditions are as follows.

(7) Measurement of coating amount variation The coating amount variation was determined using the amount of flurbiprofen in the film agent as an index.
That is, flurbiprofen in the film agent was quantified one by one by high performance liquid chromatography. The relative standard deviation was calculated from the flurbiprofen content of 30 film agents obtained by one coating and drying, and the variation in coating amount was obtained.

(8) Results Table 6 shows the results.

Table 6 shows the variation in coating amount using the thixotropy index (TI) of the preparation solutions of Examples and Comparative Examples and the content of flurbiprofen in the film preparation as indices.
As can be seen from Table 6, by setting the thixotropy index to 0.1 or more, the relative standard deviation of the coating amount variation could be 4.7% or less.
Moreover, as shown in Reference Example 1, the preparation solution having a thixotropy index of 0.01 could not be applied at all.

1. Print version 2. Application part of film for oral administration

Claims (6)

  A method for producing a film preparation for oral administration, wherein the drug-containing layer is formed by screen printing of a drug-containing liquid having a thixotropic index of 0.1 to 0.7.   The method for producing a film preparation for oral administration according to claim 1, wherein the thixotropic index of the drug-containing liquid is 0.15 or more and 0.6 or less.   The method for producing a film preparation for oral administration according to claim 1 or 2, wherein the drug-containing layer has functional layers on both sides or one side.   The method for producing a film preparation for oral administration according to claim 3, wherein the functional layer is a layer containing a water-soluble polymer.   The method for producing a film preparation for oral administration according to any one of claims 1 to 4, wherein the drug-containing liquid is a liquid containing a water-soluble polymer, a drug, and a thixotropic substance.   The film formulation for oral administration obtained by the manufacturing method in any one of Claims 1-5.