Film-form preparation and method for producing the same

Abstract

The present invention provides a film-form preparation having a rapid dissolution profile in the mouth and sufficient film strength, and also having excellent appearance and feel. More specifically, the present invention provides a film-form preparation including: a water-soluble and a polar organic solvent-soluble edible polymer; and polar organic solvent-insoluble drug particles.

Claims

1. A film-form preparation comprising: a water-soluble and polar organic solvent-soluble edible polymer; and polar organic solvent-insoluble drug particles, wherein said polar organic solvent-insoluble drug particles are contained in a particulate state within the film-form preparation, wherein a particle size of the drug particles is 0.1 to 60 μm, and wherein the content of the drug particles is 0.1 to 60 wt % of the total content of solids contained in the film-form preparation.

2. The film-form preparation according to claim 1, wherein the edible polymer is a solid at normal temperatures.

3. The film-form preparation according to claim 1, wherein the edible polymer is polyvinyl pyrrolidone and/or hydroxypropyl cellulose.

4. The film-form preparation according to claim 3, wherein a molecular weight of the polyvinyl pyrrolidone ranges from 2,500 to 3,000,000.

5. The film-form preparation according to claim 3, wherein a molecular weight of the hydroxypropyl cellulose ranges from 10,000 to 1,150,000.

6. The film-form preparation according to claim 3, wherein the hydroxypropyl cellulose has a hydroxypropoxy group-substitution degree of 50 to 100%.

7. The film-form preparation according to claim 1, wherein a solubility parameter of the polar organic solvent is not less than 9.7.

8. A method for producing a film-form preparation including a water-soluble and polar organic solvent-soluble edible polymer and polar organic solvent-insoluble drug particles, and the method comprising: preparing a liquid dispersion of a drug containing the edible polymer, the drug particles, and a polar organic solvent; forming the liquid dispersion of the drug into a thin layer; and drying the thin layer, wherein the particle size of the drug particles is 0.1 to 60 μm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a schematic drawing showing one example of an embodiment of the film-form preparation of the present invention;

(2) FIG. 2 is a schematic drawing showing the tack duration test;

(3) FIG. 3 is an SEM image of potassium guaiacolsulfonate particles;

(4) FIG. 4 is an SEM image of potassium guaiacolsulfonate particles A;

(5) FIG. 5 is an SEM image of potassium guaiacolsulfonate particles B;

(6) FIG. 6 is an SEM image of potassium guaiacolsulfonate particles C;

(7) FIG. 7 is an SEM image of glutathione (reduced form) particles;

(8) FIG. 8 is an SEM image of aminophylline particles;

(9) FIG. 9 is a micrograph of the surface of the film-form preparation of Example 1;

(10) FIG. 10 is a micrograph of the surface of the film-form preparation of Example 2;

(11) FIG. 11 is a micrograph of the surface of the film-form preparation of Example 3;

(12) FIG. 12 is a micrograph of the surface of the film-form preparation of Example 4;

(13) FIG. 13 is a micrograph of the surface of the film-form preparation of Example 5;

(14) FIG. 14 is a micrograph of the surface of the film-form preparation of Example 6;

(15) FIG. 15 is a micrograph of the surface of the film-form preparation of Example 7;

(16) FIG. 16 is a micrograph of the surface of the film-form preparation of Example 8;

(17) FIG. 17 is a micrograph of the surface of the film-form preparation of Example 9;

(18) FIG. 18 is a micrograph of the surface of the film-form preparation of Example 10;

(19) FIG. 19 is a micrograph of the surface of the film-form preparation of Example 11;

(20) FIG. 20 is a micrograph of the surface of the film-form preparation of Example 12;

(21) FIG. 21 is a micrograph of the surface of the film-form preparation of Example 13;

(22) FIG. 22 is a micrograph of the surface of the film-form preparation of Comparative Example 1;

(23) FIG. 23 is a micrograph of the surface of the film-form preparation of Comparative Example 2;

(24) FIG. 24 is a micrograph of the surface of the film-form preparation of Comparative Example 3;

(25) FIG. 25 is a micrograph of the surface of the film-form preparation of Comparative Example 4;

(26) FIG. 26 is a micrograph of the surface of the film-form preparation of Comparative Example 5;

(27) FIG. 27 is a micrograph of the surface of the film-form preparation of Comparative Example 6; and

(28) FIG. 28 is a micrograph of the surface of the film-form preparation of Comparative Example 7.

MODES FOR CARRYING OUT THE INVENTION

(29) The present invention is described in detail through the following examples, but is by no means limited to those examples.

(30) The various drug particles used in the Examples and Comparative Examples were obtained passing the powder through a 32 μm, 53 μm, 90 μm sieve after pulverization, or obtained fine particles by a jet mill (product of Hosokawa Micron Group, spiral jet mill model 50AS) or a spray dryer (product of Büchi Labortechnik AG, mini spray dryer model B-290) after pulverization. The particle sizes of these drug particles were measured by electron microscope (product of Hitachi High-Technologies Corp., model TM-1000) and the 50 vol % average particle size was calculated from the measurement results of 200 particles. This value was used as the particle size index of the particles.

(31) Table 2 shows the 50 vol % average particle size and standard deviation of the drug particles. Images of these particles are shown in FIGS. 3 to 8.

(32) TABLE-US-00002 TABLE 2 50 vol Standard % average particle deviation Drug particles size [um] [um] Potassium guaiacolsulfonate particles 5.0 1.4 Potassium guaiacolsulfonate particles A 2.1 0.3 Potassium guaiacolsulfonate particles B 40.4 9.4 Potassium guaiacolsulfonate particles C 80.4 25.8 Glutathione (reduced form) particles 5.3 0.9 Aminophyllin particles 4.3 0.9

Example 1

(33) After 0.35 parts by weight of polyethylene glycol (PEG400) was added to 12.0 parts by weight of ethanol and stirred well, 6.65 parts by weight of HPC (product of Nippon Soda Co., Ltd., brand name: Nisso HPC SSL) with a molecular weight of approximately 30,000 and a hydroxypropoxy group-substitution degree of 53.4 to 77.5% was added, stirred, and dissolved using a rolling mixer. Then 3.0 parts by weight of previously sized potassium guaiacolsulfonate particles were added and dispersed by sonication to prepare a liquid dispersion of the drug. After the liquid dispersion of the drug was adequately degassed, it was spread onto a polyester release film and dried to prepare a film with a thickness of approximately 70 μm. The resulting film was peeled from the polyester release film and cut into 4 cm.sup.2 rectangles to obtain the film-form preparation of Example 1.

Example 2

(34) The film-form preparation of Example 2 was obtained using the same procedure as in Example 1 except PVP (product of Wako Pure Chemical Industries Co., Ltd., reagent name: polyvinyl pyrrolidone K90) with a molecular weight of 1,050,000 to 1,200,000 was used in place of the HPC to make the composition shown in Table 3.

Example 3

(35) The film-form preparation of Example 3 was obtained using the same procedure as in Example 1 except that acetone was used in place of the ethanol to make the composition shown in Table 3.

Example 4

(36) The film-form preparation of Example 4 was obtained using the same procedure as in Example 2 except that acetone was used in place of the ethanol to make the composition shown in Table 3.

Example 5

(37) The film-form preparation of Example 5 was obtained using the same procedure as in Example 1 except previously sized glutathione (reduced form) particles were used in place of the potassium guaiacolsulfonate particles to make the composition shown in Table 3.

Example 6

(38) The film-form preparation of Example 6 was obtained using the same procedure as in Example 1 except previously sized aminophylline particles were used in place of the potassium guaiacolsulfonate particles to make the composition shown in Table 3.

Example 7

(39) The film-form preparation of Example 7 was obtained using the same procedure as in Example 6 except PVP (product of Wako Pure Chemical Industries Co., Ltd., reagent name: polyvinyl pyrrolidone K90) with a molecular weight of 1,050,000 to 1,200,000 was used in place of the HPC to make the composition shown in Table 3.

(40) TABLE-US-00003 TABLE 3 Examples [Parts by weight] Component 1 2 3 4 5 6 7 HPC 6.65 — 6.65 — 6.65 6.65 — PVP — 6.65 — 6.65 — — 6.65 PEG400 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Potassium 3.00 3.00 3.00 3.00 — — — guaiacolsulfonate particles Glutathione — — — — 3.00 — — (reduced form) particles Aminophyllin — — — — — 3.00 3.00 particles Ethanol 12.00  19.00  — — 12.00  12.00  19.00  Acetone — — 12.00  19.00  — — —

Example 8

(41) After 0.35 parts by weight of polyethylene glycol (PEG400) was added to 12.0 parts by weight of ethanol and stirred well, 6.65 parts by weight of HPC (product of Nippon Soda Co., Ltd., brand name: Nisso HPC SSL) with a molecular weight of approximately 30,000 and a hydroxypropoxy group-substitution degree of 53.4 to 77.5% was added, stirred, and dissolved using a rolling mixer. Then 3.0 parts by weight of previously sized potassium guaiacolsulfonate particles A were added and dispersed by sonication to prepare a liquid dispersion of the drug. After the liquid dispersion of the drug was adequately degassed, it was spread onto a polyester release film and dried to prepare a film with a thickness of approximately 70 μm. The resulting film was peeled from the polyester release film and was cut into 4 cm.sup.2 rectangles to obtain the film-form preparation of Example 8.

Examples 9, 10

(42) The film-form preparations of Example 9 and Example 10 were obtained using the same procedure as in Example 8 except previously sized potassium guaiacolsulfonate particles B and C were respectively used in place of the potassium guaiacolsulfonate particles A to make the compositions shown in Table 4.

Examples 11 to 13

(43) The film-form preparations of Examples 11 to 13 were obtained using the same procedure as in Example 8 except for making the compositions shown in Table 4.

(44) TABLE-US-00004 TABLE 4 Examples [Parts by weight] Component 8 9 10 11 12 13 HPC 6.65 6.65 6.65 8.65 3.65 1.65 PEG400 0.35 0.35 0.35 0.35 0.35 0.35 Potassium 3.00 — — 1.00 6.00 8.00 guaiacolsulfonate particles A Potassium — 3.00 — — — — guaiacolsulfonate particles B Potassium — — 3.00 — — — guaiacolsulfonate particles C Ethanol 12.00  12.00  12.00  15.00  15.00  15.00 

Comparative Example 1

(45) First 0.35 parts by weight of polyethylene glycol (PEG400), 3.0 parts by weight of previously sized potassium guaiacolsulfonate particles, and 15.0 parts by weight of distilled water were added to 6.65 parts by weight of HPC (product of Nippon Soda Co., Ltd., brand name: Nisso HPC SSL) with a molecular weight of approximately 30,000 and a hydroxypropoxy group-substitution degree of 53.4 to 77.5%, and the mixture was stirred and dissolved using a rolling mixer. After the liquid dispersion of the drug was adequately degassed, it was spread onto a polyester release film and dried to prepare a film with a thickness of approximately 70 μm. The resulting film was peeled from the polyester release film and was cut into 4 cm.sup.2 rectangles to obtain a film-form preparation of the Comparative Example 1.

Comparative Examples 2 to 4

(46) The film-form preparations of Comparative Examples 2 to 4 were obtained using the same procedure as in Comparative Example 1 except PVP (product of Wako Pure Chemical Industries Co., Ltd., reagent name: polyvinyl pyrrolidone K90) with a molecular weight of 1,050,000 to 1,200,000 was used in Comparative Example 2, HPMC (product of Shin-etsu Chemical Co., Ltd., brand name: TC-5E) having a methoxy group-substitution degree of 28.0 to 30.0% and a hydroxypropoxy group-substitution degree of 7.0 to 12.0% with a weight average molecular weight of 16,000 was used in Comparative Example 3, and pullulan (product of Hayashibara Shoji INC., brand name: food additive pullulan) with a weight average molecular weight of 200,000 was used in Comparative Example 5, in place of the HPC to make the composition shown in Table 5.

Comparative Example 5

(47) The film-form preparation of Comparative Example 5 was obtained using the same procedure as in Comparative Example 1 except previously sized glutathione (reduced form) particles were used in place of the potassium guaiacolsulfonate particles to make the composition shown in Table 5.

Comparative 6

(48) The film-form preparation of Comparative Example 6 was obtained using the same procedure as in Comparative Example 1 except previously sized aminophylline particles were used in place of the potassium guaiacolsulfonate particles to make the composition shown in Table 5.

Comparative Example 7

(49) The film-form preparation of Comparative Example 7 was obtained using the same procedure as in Comparative Example 6 except PVP (product of Wako Pure Chemical Industries Co., Ltd., reagent name: polyvinyl pyrrolidone K90) with a molecular weight of 1,050,000 to 1,200,000 were used in place of the HPC to make the composition shown in Table 5.

(50) TABLE-US-00005 TABLE 5 Comparative Examples [parts by weight] Component 1 2 3 4 5 6 7 HPC 6.65 — — — 6.65 6.65 — PVP — 6.65 — — — — 6.65 HPMC — — 6.65 — — — — Pullulan — — — 6.65 — — — PEG400 0.35 0.35 0.35 0.35 0.35 0.35 0.35 Potassium guaiacolsulfonate particles 3.00 3.00 3.00 3.00 — — — Glutathione (reduced form) particles — — — — 3.00 — — Aminophyllin — — — — — 3.00 3.00 Distilled water 15.00  18.60  18.60  18.60  15.00  15.00  18.60  Ethanol — — — — — — —
[Test Methods]

(51) Measurements and evaluations were carried out on the film-form preparations prepared in these Examples and Comparative Examples for release properties during production, film flexibility, film strength, gummy sensation in the mouth, dissolution profile in the mouth, feel when touched by the fingers, and appearance by peeling test, stiffness test, tensile strength test, tack duration test, oral dissolution test, sensory test (feel), and visual observation. Images of the drug particles dispersed in the film-form preparation or drug crystals deposited in the film-form preparation were taken with a microscope. Each test method is described below.

(52) (1) Release Properties Test

(53) Samples were peeled from the polyester release films during production of each of the film-form preparations. The release properties were evaluated in the process. The evaluation criteria were as follows.

(54) 4: Can be peeled off easily

(55) 3: Can be peeled off

(56) 2: Can be peeled off with some effort

(57) 1: Can be peeled off with effort, but film tears

(58) 0: Cannot be peeled off at all

(59) (2) Stiffness Test

(60) This test was performed following the test method of “JIS L1096 Testing Methods for Woven Fabrics, 8.19 Stiffness, 8.19.1 Method A (45° cantilever method). In this test five 20 mm×150 mm test pieces were selected, and the short dimension of the test piece was aligned with the baseline of the scale on a smooth-surfaced, flat platform with one end having a 45° downward slope. Next, the test piece was gently slid in the direction of the slope by a suitable method, and when the center point of an edge of the test piece came into contact with the slope A, the position of the trailing edge was read on the scale. Stiffness is expressed as the length (mm) that the test piece was moved. Stiffness was determined by measuring the five test pieces both top up and bottom up, and both forward and backward, and then calculating the mean value.

(61) For the evaluation reference values, evaluation films minus the drug particles were prepared for each film-form preparation in the Examples and Comparative Examples (Reference Examples 1 to 6 below). The stiffness of the film in each Reference Example was considered a reference value, and the following scale was established.

(62) 4: Reference value ±10 mm

(63) 3: Reference value ±20 mm

(64) 2: Reference value ±30 mm

(65) 1: Reference value ±40 mm or more

(66) The samples evaluated as being unable to be peeled off at all in the above (1) release properties test were given a score of 0 because they could not be examined.

Reference Example 1

(67) First 0.5 parts by weight of polyethylene glycol (PEG400) and 15.0 parts by weight ethanol (99.5%) were added to 9.5 parts by weight of HPC (product of Nippon Soda Co., Ltd., brand name: Nisso HPC SSL) with a molecular weight of approximately 30,000 and a hydroxypropoxy group-substitution degree of 53.4 to 77.5%, and stirred and dissolved using a rolling mixer. After the solution was adequately degassed, it was spread onto a polyester release film and dried to prepare a film with a thickness of approximately 70 μm. The resulting film was peeled off from the polyester release film and cut into 4 cm.sup.2 rectangles to obtain Evaluation Film (1).

Reference Examples 2 to 6

(68) Evaluation Films (2) to (6) were obtained by the same procedure as in Reference Example 1 except the compositions shown in Table 6 were used. The PVP, HPMC and pullulan in Table 6 are the same as those described above.

(69) TABLE-US-00006 TABLE 6 Reference Examples [parts by weight] Component 1 2 3 4 5 6 HPC 9.5 — 9.5 — — — PVP — 9.5 — 9.5 — — HPMC — — — — 9.5 — Pullulan — — — — — 9.5 PEG400 0.5 0.5 0.5 0.5 0.5 0.5 Ethanol 15.0  23.3  — — — — Distilled water — — 18.6  23.3  23.3  23.3  Evaluation film (1)   (2)   (3)   (4)   (5)   (6)  
(3) Tensile Strength Test

(70) A small, tabletop, vertical tensile test apparatus (produced by Shimadzu Corporation, EZ TEST-100M) was used following “JIS K7127 Testing Method for Tensile Properties of Plastic Films and Sheets.” The film-form preparation was cut to a 12 mm×50 mm test sample, and the test was performed after thorough drying in a desiccator. A rate of 60 mm/min was used as the draw rate. Because almost no stretching was seen in the test samples, the tensile strength at the measured yield point was used as the tensile strength value.

(71) The test was repeated 3 times for each sample, and the mean value was recorded as the tensile strength. The tensile strength was then given a score using the following criteria.

(72) 4: 10 to 20 N

(73) 3: 5 to 10 N

(74) 2: 2 to 5 N

(75) 1: 0 to 2 N

(76) The samples evaluated as being unable to be peeled off at all in the above (1) release properties test were given a score of 0 because they could not be examined.

(77) (4) Tack Duration Test

(78) The test was performed under the environment shown in FIG. 2 using a rheometer (SUN SCIENTIFIC, CR-2000). First, a 12 mm diameter test piece 2c was adhered to a 12 mm diameter probe 2a with double-sided tape 2b. Separately, a piece of rubber 2e was mounted on the test platform 2f, and a collagen film 2d soaked with water was placed thereon. Then 200 μL of purified water was applied to the test piece, the probe 2a with the test piece 2c adhered thereto was lowered, placed in contact with the top of the collagen film 2d, and then raised. At that time, the tack duration after the initial tack, which was obtained when the probe 2a released from the collagen film 2d, was measured using slide caliper from recording paper. The criteria were as follows.

(79) 4: 0 to 10 mm

(80) 3: 10 to 15 mm

(81) 2: 15 to 20 mm

(82) 1: 20 mm or more

(83) The samples evaluated as being unable to be peeled off at all in the above (1) release properties test were cut together with the release film, and the release film side was adhered to the probe with double-sided tape. Then, the tack duration was measured in the same manner.

(84) (5) Oral Dissolution Test

(85) First 900 mL of pH 6.8 phosphate buffer was placed in a 1000 mL low glass petri dish, a stainless steel mesh basket (φ 4 mm) was inverted and submerged therein, and agitation was provided by a stirrer (300 rpm). The temperature of the liquid was maintained at 37±2° C. using a constant temperature water circulator. A test piece (4 cm.sup.2) was submerged, and concurrently a 3 cm.sup.2×3 cm.sup.2 stainless steel screen (5 mm mesh) was placed on top as a sinker. The duration from the time the test piece was submerged until the test piece had finished disintegrating was checked visually and measured with a stop watch.

(86) The measurement of each sample was repeated 3 times, and the mean was used as the oral dissolution time. The oral dissolution time was then given a score using the following criteria.

(87) 4: 0 to 10 sec

(88) 3: 10 to 15 sec

(89) 2: 15 to 20 sec

(90) 1: 20 sec or longer

(91) The samples evaluated as being unable to be peeled off at all in the above (1) release properties test were given a score of 0 because they could not be examined.

(92) (6) Sensory Test (Feel)

(93) The cut film-form preparations from the Examples and Comparative Examples were evaluated for the unpleasant sensation of a sticky sensation on the surface by actually tracing a circle thereon with the fingers for 5 sec. The criteria were as follows.

(94) 4: No sticky sensation

(95) 3: Slightly sticky but not unpleasant

(96) 2: Unpleasant sticky sensation

(97) 1: Very sticky, and film remains on the fingers.

(98) (7) Appearance (Visual)

(99) The cut film-form preparations from the Examples and Comparative Examples were evaluated visually for film uniformity. The criteria were as follows.

(100) 4: The film is uniform

(101) 3: Fine deposits of crystals or fine aggregates of particles are visible in some places

(102) 2: Large deposits of crystals or large aggregates of particles are visible in some places

(103) 1: Deposits of crystals or aggregates of particles are visible in the majority of places

(104) Images of the drug particles or deposited drug crystals in the film of the respective film-form preparations according to Comparative Examples 1 to 7 and Examples 1 to 13 were taken with a microscope (product of Keyence Corp., model VHX-600). Each of the results was shown in FIGS. 7 to 26.

(105) Table 7 shows the results of the release properties test, stiffness test, tensile strength test, tack duration test, oral dissolution test, sensory test (feel), and appearance (visual observation) performed on the film-form preparations of Examples and Comparative Examples. Total score of these seven evaluation items was obtained, and the film-form preparations of Examples and Comparative Examples were relatively evaluated based on the total scores.

(106) TABLE-US-00007 TABLE 7 Appearance Release Stiffness Tensile Tack Oral Sensory (visual properties Results Evaluation film strength duration dissolution (feel) observation) Total Examples 1 4 4 (1) 4 4 4 4 4 28 2 4 4 (2) 4 3 3 4 4 26 3 4 4 (1) 4 4 4 4 4 28 4 4 4 (2) 4 3 3 4 4 26 5 4 4 (1) 4 4 4 4 4 28 6 4 4 (1) 4 3 4 4 4 27 7 4 4 (2) 4 3 4 4 4 27 8 4 4 (1) 4 4 4 4 4 28 9 4 3 (1) 3 3 4 4 4 25 10 4 4 (1) 2 3 4 4 4 25 11 4 4 (1) 4 3 4 4 4 27 12 4 4 (1) 3 3 4 4 4 26 13 4 4 (1) 2 3 4 4 4 25 Comparative 1 2 3 (3) 2 4 3 3 1 18 Examples 2 2 2 (4) 1 3 4 2 2 16 3 2 2 (5) 1 4 4 3 2 18 4 2 2 (6) 1 4 3 3 1 16 5 1 4 (3) 3 4 1 3 1 17 6 0 0 (3) 0 4 0 3 1 8 7 0 0 (4) 0 3 0 2 1 6

(107) As shown in Table 7, all drug particles in the film-form preparations of the Examples were contained in a particulate state, and most of the drug particles existed with an ordered particle size in a range of 1 to 60 μm. The total evaluation scores ranged from 25 to 28.

(108) Meanwhile, in the film-form preparations according to Comparative Examples, the drug particles were contained in a dissolved or recrystallized state. The total evaluation scores ranged from 6 to 18.

INDUSTRIAL APPLICABILITY

(109) The film-form preparation of the present invention can stably contain a sufficient quantity of drug expressing a rapid dissolution profile in the mouth because the drug particles are dispersed in a particulate state, and can have sufficient film strength, a satisfactory sensation when touched by the fingers, film appearance, and the like.

(110) Furthermore, the production method for the film-form preparation of the present invention enables the drug particles to be dispersed and carried in the film-form preparation without the need to dissolve the same in solution, and therefore a film-form preparation containing the drug in a particulate state can be produced efficiently, and the size and shape of the drug particles can be controlled thereby.

EXPLANATION OF SYMBOLS

(111) 1a Drug particles 1b Base material 2a Probe 2b Double-sided tape 2c Test piece 2d Collagen film 2e Rubber 2f Test platform