WO2013002331A1 - 皮膚治療用微細針集積型製剤 - Google Patents
皮膚治療用微細針集積型製剤 Download PDFInfo
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- WO2013002331A1 WO2013002331A1 PCT/JP2012/066546 JP2012066546W WO2013002331A1 WO 2013002331 A1 WO2013002331 A1 WO 2013002331A1 JP 2012066546 W JP2012066546 W JP 2012066546W WO 2013002331 A1 WO2013002331 A1 WO 2013002331A1
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- microneedle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
Definitions
- the target substance is not particularly limited as long as it is a substance effective for the prevention or treatment of skin aging or treatment of skin scar and can be dissolved or dispersed in the above-mentioned polymer substance.
- the target substance may be any of various growth factors that act on skin cells, or substances that promote the production of the growth factors by skin cells.
- the target substance may further contain, as substances other than bFGF and aFGF, substances having or having the same therapeutic effect on skin aging or therapeutic effect on skin scar at the same time.
- the first raw material mixture is placed on a mold, and if necessary, a coating pressure such as a squeegee or the like is used to apply a coating pressure to fill the holes formed in the mold.
- a centrifugal force may be applied to the mold using a centrifuge or the like.
- the insertion direction length of the second portion of the microneedle is preferably 100 ⁇ m or more, more preferably 200 ⁇ m. The above, more preferably 220 ⁇ m or more.
- the insertion direction length of the second portion of the fine needle is preferably 400 ⁇ m or less, more preferably 300 ⁇ m or less, and still more preferably 250 ⁇ m or less.
- the insertion direction length of the first portion of the microneedle may be adjusted so that the insertion direction length of the second portion is optimal.
- a predetermined impact force is applied to the skin to pierce the microneedle from the skin into the body.
- the application of the impact force can be performed by causing the front surface of the microneedle accumulation type preparation to collide with the skin at high speed.
- the pressure (collision pressure) with which the microneedle accumulation type preparation collides with the skin is 5 to 40 N, preferably 10 to 35 N, more preferably 15 to 30 N.
- the impact pressure of the microneedle accumulation type preparation is less than 15 N, the penetration depth of the microneedles becomes shallow. In addition, even if the impact pressure of the microneedle accumulation type preparation is increased beyond 35 N, the microneedle penetration depth does not increase so much.
- the method of causing the microneedle accumulation type preparation to collide with the skin For example, fix the surface (hereinafter referred to as “back side”) of the microneedle-accumulated formulation on the side where the microneedles are not formed on the tip of the rod, and place it in a suitable guide cylinder sized to slide the rod back and forth
- the rod may be driven at high speed with the front surface of the microneedle accumulation type preparation directed to the skin.
- the driving of the rod can be performed using, for example, an elastic body such as a spring and rubber.
- the pressure of the secondary pressurization is 0.5 to 2.5 N, preferably 1 to 2.5 N, more preferably 1.5 to 2.5 N. If the pressure is less than 0.1 N, the inserted microneedle may be pushed back and the first portion of the microneedle may come out of the outside. In addition, it is not preferable to increase the pressure over 2.5 N because it causes a burden such as pain on the skin.
- the pressure of the secondary pressure is a force per an area of 1.77 cm 2 .
- Example 3 The bFGF-containing soluble microneedles prepared in Examples 1 and 2 were incubated at minus 80 ° C., 4 ° C., 23 ° C. and 40 ° C. for 3 months, and one week, one month and three months after the start of the experiment The content of bFGF was measured later.
- the content of bFGF in a soluble microneedle stored at ⁇ 80 ° C. is defined as 100%, and the results are shown as relative contents under conditions of 4 ° C., 23 ° C. and 40 ° C.
- the following numerical values are mean value ⁇ SD (standard deviation).
- the content of bFGF in the soluble microneedles of Example 1 after one week under each storage temperature condition is 101.6 ⁇ 4.7% (4 ° C.), 100.9 ⁇ 8.8% (23 ° C.) ), 103.3 ⁇ 4.7% (40 ° C.).
- the content of bFGF in the soluble microneedles of Example 2 after one week under each storage temperature condition is 100.6 ⁇ 2.7% (4 ° C.), 99.5 ⁇ 1.1% (23 ° C.) ), 99.5 ⁇ 1.5% (40 ° C.).
- the content of bFGF in the soluble microneedles of Example 1 after one month under each storage temperature condition is 100.7 ⁇ 2.0% (4 ° C.), 98.7 ⁇ 4.9% (23 ° C.) ), 102.8 ⁇ 2.7% (40 ° C.).
- the content of bFGF in the soluble microneedles of Example 2 after one month under each storage temperature condition is 99.4 ⁇ 2.9% (4 ° C.), 97.7 ⁇ 4.5% (23 ° C.) ), 97.6 ⁇ 4.9% (40 ° C.).
- the content of bFGF in the soluble microneedles of Example 1 after 3 months under each storage temperature condition is 98.7 ⁇ 7.1% (4 ° C.), 99.0 ⁇ 7.0% (23 ° C.) ), 100.7 ⁇ 7.6% (40 ° C.).
- the content of bFGF in the soluble microneedles of Example 2 after 3 months under each storage temperature condition is 107.6 ⁇ 1.7% (4 ° C.), 101.2 ⁇ 4.3% (23 ° C.) ), 105.7 ⁇ 6.4% (40 ° C.).
- the bFGF-containing soluble microneedles of Examples 1 and 2 were also shown to be very stable under a wide range of storage conditions.
- a 10: 1 mixture of cellulose acetate and hydroxypropyl cellulose is put in the die of a single-shot tableting machine (Shishi Hashi Seiki, HANDTAB 100), and the diameter is 1.5 cm and the thickness is about 2 at a tableting pressure of about 10 kN.
- a base support of .0 mm was made.
- a viscous liquid prepared by adding 150 microliters of purified water to 50 mg of sodium chondroitin sulfate and 100 mg of dextran 40 was coated on a substrate support, covered on a female mold, and dried under pressure.
- Example 5 A Wistar male rat weighing about 330 grams was fixed on a surgical table under pentobarbital anesthesia, and an incision of about 3 cm was made in the depiled abdominal skin with a scalpel. Medical silk suture No. Three needle sutures were performed using 3 (Murase suture, Inc.). On the second postoperative day, thread removal was performed. The rats were divided into two groups, and the bFGF-containing soluble microneedle-accumulating patch preparation prepared in Example 4 was administered to the skin at the suture site one week after the operation in the first group of rats.
- the content of bFGF per patch is 0.2 ⁇ g
- the width of the scar is less than half of the control, and when it is 1.0 ⁇ g or more, the scar is improved to such an extent that scars hardly exist.
- the image of the sample was taken into a computer and the width of the scar in the dermal layer was measured.
- 1117.7 ⁇ 181.6 ⁇ m in the control group 527.3 ⁇ 146.0 ⁇ m in 0.2 ⁇ g, 251.5 ⁇ 46.3 ⁇ m in 0.5 ⁇ g, 139.0 ⁇ 40.5 ⁇ m in 1.0 ⁇ g, At 2.0 ⁇ g, the result was 119.0 ⁇ 13.4 ⁇ m (FIG. 5).
- the scar width was statistically significantly narrowed at 0.2 ⁇ g or more compared to the control group, and the effect was dose-dependent, but the difference was small at 0.5 ⁇ g or more Became.
- Example 6 A viscous liquid was prepared by adding 225 microliters of purified water to 35 mg of a lyophilized bFGF preparation "Fiblast Spray 500" (trade name, Kaken Pharmaceutical), 22.5 mg of chondroitin sodium sulfate, and 45 mg of dextran 40. The viscous liquid was applied on a female die having 300 inverse conical pores with a depth of about 500 microns and an opening diameter of about 300 microns per square centimeter.
- the female mold was filled under pressurized conditions. After drying, a viscous liquid prepared by adding 150 ⁇ l of purified water to 100 mg of sodium chondroitin sulfate and 50 mg of dextran was coated on a female mold, and filled into the female mold under pressure. First, about 0.30 g of a 100: 10: 5 mixture of cellulose acetate, hydroxypropyl cellulose and iron powder was placed in a single-shot tablet mill. Next, about 0.25 g of a 100: 10 blend of cellulose acetate and hydroxypropyl cellulose is placed thereon to give a substrate support having a diameter of 1.5 cm and a thickness of about 2.0 mm at a tableting pressure of about 10 kN. A two-layer lock was created.
- a viscous liquid prepared by adding 150 ⁇ l of purified water to 100 mg of sodium chondroitin sulfate and 50 mg of dextran 40 was coated on a substrate support, covered on a female die, and dried under pressure. After 6 hours, the substrate support was pulled away from the female mold to obtain a patch preparation in which 300 microneedles were constructed in an array.
- the obtained patch preparation was inserted in advance into a polypropylene PTP packaging container having a lumen bottom diameter of 1.6 cm and a height of 1.0 cm. I put it on a .5 cm polypropylene ring. After covering the aluminum sheet, it was sealed by pressing and heating and stored until use. It was about 0.3 microgram when the amount of bFGF contained in this two-layer fine needle accumulation type patch formulation was measured.
- Example 7 The bFGF-containing soluble microneedle-accumulating patch preparation prepared in Example 6 was used for the treatment of the following Cases 1 to 5. Explain symptoms, administration conditions and results.
- Case 1 57 years old, female. Sixteen bFGF-containing fine needles were applied to the left and right sides of the forehead with a pressure-sensitive adhesive, maintained at the same site for about 1 minute, then removed and coated with a hydrocolloid coating material. From the 3rd day after the treatment, follow-up was observed only with topical application of a light-blocking cream. Immediately after the treatment, the vertical wrinkles became shallow and the skin texture was improved, and in the third month after the treatment, the skin texture of the forehead was improved and the lateral wrinkles, intercostal space became shallow (Fig. 6A) , B, C).
- Case 2 50 years old, female.
- Three pieces of bFGF-containing microneedles were applied to the eyelid (the so-called crow's foot mark) of the left extraocular eyelid by applying a pressure-sensitive adhesive, keeping them in the same region for 3 minutes, and removing and coating with a hydrocolloid coating material. From the 3rd day after the treatment, follow-up was observed only with topical application of a light-blocking cream. Immediately after the treatment, the eyelids become shallow and the texture of the skin is improved, and at the third month after treatment, the eyelids in the corner of the left outer eye (the so-called crow's footprints) disappear almost (FIGS. 7A, B, C).
- Case 3 61 years old, female.
- Eight bFGF-containing microneedles were applied to the back of the left hand by pressing and applying the same for 3 minutes and then removed and coated with a hydrocolloid coating material.
- seven bFGF-containing fine needles were further applied around the same site.
- Case 4 63 years old, male. Ten pieces of bFGF-containing microneedles were pressed onto the right-handed back, maintained at the same site for 3 minutes and then removed and coated with a hydrocolloid coating. The erythema observed immediately after bFGF-containing microneedle application almost disappeared in 5 days in this case, and after 3 days of treatment, it was followed up with external application of a light-shielding cream only. Immediately after the treatment, the skin texture was improved, and at the third month after treatment, the protruding veins were flattened and the atrophyed skin was also restored in thickness, and the effect of the bFGF-containing fine needle was extremely high. (FIGS. 9A, B, C). No adverse events such as pigmentation were observed in this case.
- a viscous concentrate prepared by adding 300 microliters of purified water to 100 mg of sodium chondroitin sulfate was coated on a female die.
- Cellulose acetate for tablets was placed in a die of a single-shot tableting machine, and a circular tablet base with a diameter of 1.5 cm and a thickness of about 2 mm prepared at a tableting pressure of about 10 kN was covered, dried and cured. Thereafter, the base was removed from the female mold to obtain a microneedle-accumulated preparation containing no target substance.
- the area of the skin-contacting side (front side) of the microneedle accumulation type preparation for penetration test is 1.77 cm 2 .
- Reference Example 2 In vitro secondary pressure test
- a microneedle accumulation type preparation for penetration test was produced in the same manner as in Reference Example 1, and microneedles were inserted into rat and human skin in vitro at a collision pressure of 21.3 N. Then, the back of the microneedle accumulation type formulation was subsequently pressurized (secondary pressurization). At that time, the pressure and pressurization time were changed to measure how the depth of penetration of the fine needle changed. The results are shown in FIG.
- Reference Example 3 In vivo secondary pressure test
- a microneedle accumulation type preparation for insertion test is manufactured in the same manner as in Reference Example 1, and the microneedle accumulation type preparation is caused to collide with the abdominal hair removal skin of a rat under pentobarbital anesthesia under a collision pressure of 21.3 N, in Fine needles were inserted into the skin of rats in vivo. Then, the back of the microneedle accumulation type formulation was subsequently pressurized (secondary pressurization). At that time, the pressure and pressurization time were changed to measure how the depth of penetration of the fine needle changed. The results are shown in FIG.
- the microneedle-accumulating type preparation was pierced into the skin under a collision pressure of 21.3 N to 40.2 N, and then was loaded for 3 minutes at a pressure of 2.5 N as a secondary pressure.
- the drug is localized at a portion of 233 ⁇ m from the tip of the fine needle, it becomes possible to achieve a value of 100% as the bioavailability of the target substance.
- a viscous thick liquid prepared by adding 400 microliters of purified water to 440 mg of sodium chondroitin sulfate was coated on a female die.
- Cellulose acetate for tablets was placed in a die of a single-shot tableting machine, and a tablet base of about 1.5 cm in diameter and about 2 mm in thickness prepared at a tableting pressure of about 10 kN was covered thereon and dried and cured. Thereafter, the base was peeled from the female mold to obtain two types of microneedle-accumulating preparations having microneedles containing insulin as a target substance.
- microneedles of the two types of two-layered microneedle-accumulated patch preparations prepared were observed with a video microscope (VH-5500, manufactured by Keyence Corporation), and the length from the tip of the first portion colored in blue was measured. It was 181.2 ⁇ 4.2 micrometers and 209.5 ⁇ 3.9 micrometers.
- the insulin content in both formulations was 1.58 ⁇ 0.03 and 1.72 ⁇ 0.13 IU.
- the result of having verified the effectiveness by administering to the hair removal abdominal skin of a rat is shown in FIG.
- 1.0 unit of insulin solution was administered to rats by subcutaneous injection.
- the measurement results of the temporal transition of the circulating plasma glucose concentration in rats are shown in FIG. ⁇ : data for injections, ⁇ ⁇ ⁇ and ⁇ : two-layer microneedle accumulation patch formulations with about 180 microns and about 210 microns filling length.
- the relative physiological availability (RPA) was 98.07 ⁇ 0. It was 8% and 98.08 ⁇ 3.1%.
- 1 ... support, 2 ... fine needle, 21 first part, 22 second part, 3 ... tip part, 4 ... bottom, 5 ... boundary surface.
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Abstract
Description
該目的物質が皮膚老化の予防又は治療、又は皮膚瘢痕の治療のために有効な物質である、
皮膚治療用微細針集積型製剤を提供する。
凍結乾燥bFGF製剤「フィブラストスプレー500」(商品名、科研製薬)の170mgおよびコンドロイチン硫酸ナトリウム(株式会社マルハニチロ食品)の150mgに精製水450マイクロリットルを加えて粘調液を作成した。1平方センチメートルあたりに深さ約500ミクロン、開口部直径約300ミクロンの逆円錐状の細孔を225個有するメス型の上にこの粘調液を塗布し、加圧条件下でメス型に充填した。乾燥後、メス型から取り出し、225本の微細針を得た。
凍結乾燥bFGF製剤「フィブラストスプレー500」(商品名、科研製薬)の170mgおよび「デキストラン70」(商品名、名糖産業株式会社)の150mgに精製水450マイクロリットルを加えて粘調液を作成した。1平方センチメートルあたりに深さ約500ミクロン、開口部直径約300ミクロンの逆円錐状の細孔を225個有するメス型の上にこの粘調液を塗布し、加圧条件下でメス型に充填した。乾燥後、メス型から取り出し、225本の微細針を得た。
実施例1および2で作成したbFGF含有溶解性微細針を3ヶ月間にわたり、マイナス80℃、4℃、23℃および40℃にてインキュベートを行い、実験開始1週間後、1ヶ月後および3ヶ月後にbFGFの含有量を測定した。マイナス80℃で保存した溶解性微細針中におけるbFGFの含有率を100%とし、4℃、23℃、40℃の各条件下における相対的な含有率として表した結果を示す。なお、以下の数値は平均値±SD(標準偏差)である。
各保存温度条件下の1週間後における実施例2の溶解性微細針中のbFGFの含有率は、100.6±2.7%(4℃)、99.5±1.1%(23℃)、99.5±1.5%(40℃)であった。
各保存温度条件下の1ヶ月後における実施例1の溶解性微細針中のbFGFの含有率は、100.7±2.0%(4℃)、98.7±4.9%(23℃)、102.8±2.7%(40℃)であった。
各保存温度条件下の1ヶ月後における実施例2の溶解性微細針中のbFGFの含有率は、99.4±2.9%(4℃)、97.7±4.5%(23℃)、97.6±4.9%(40℃)であった。
各保存温度条件下の3ヶ月後における実施例1の溶解性微細針中のbFGFの含有率は、98.7±7.1%(4℃)、99.0±7.0%(23℃)、100.7±7.6%(40℃)であった。
各保存温度条件下の3ヶ月後における実施例2の溶解性微細針中のbFGFの含有率は、107.6±1.7%(4℃)、101.2±4.3%(23℃)、105.7±6.4%(40℃)であった。
凍結乾燥bFGF製剤「フィブラストスプレー500」(商品名、科研製薬)の仕込み量を50mgから1.0mgまで変え、コンドロイチン硫酸ナトリウムの5.0mg、デキストラン40(商品名、名糖産業株式会社)の10mgに精製水45~30マイクロリットルを加えて4種類の粘調液を作成した。1平方センチメートルあたりに深さ約500ミクロン、開口部直径約300ミクロンの逆円錐状の細孔を225個有するメス型の上にこの粘調液を塗布し、加圧条件下でメス型に充填し、乾燥させた。
体重約330グラムのWistar系雄性ラットをペントバルビタール麻酔下、手術台に固定し、外科用メスで除毛腹部皮膚に約3cmの切開を入れた。医療用絹製縫合糸No.3(株式会社村瀬縫合糸)を用いて3針縫合を行った。術後2日目に抜糸を行った。ラットを2群に分け、そのうちの第1群のラットには術後1週間後に実施例4で作成したbFGF含有溶解性微細針集積型パッチ製剤を縫合部位の皮膚に投与した。
凍結乾燥bFGF製剤「フィブラストスプレー500」(商品名、科研製薬)の35mg、コンドロイチン硫酸ナトリウムの22.5mg、デキストラン40の45mgに精製水225マイクロリットルを加えて粘調液を作成した。1平方センチメートルあたりに深さ約500ミクロン、開口部直径約300ミクロンの逆円錐状の細孔を300個有するメス型の上にこの粘調液を塗布した。
実施例6で作成したbFGF含有溶解性微細針集積型パッチ製剤を次の症例1~5の治療に使用した。症状、投与条件及び結果を説明する。
57歳、女性。額部にbFGF含有微細針16枚を左右に圧挺貼布、約1分間同部位に維持した後に除去してハイドロコロイド被覆材で被覆した。治療後は3日目からは遮光クリームの外用のみで経過観察した。治療直後から縦皺が浅くなるとともに皮膚の肌理の改善効果が認められ、治療後3月目に額の皮膚の肌理の改善と横額の横皺、眉間の縦皺が浅くなった(図6A、B、C)。
50歳、女性。左外眼角部の皺(いわゆるカラスの足跡)に対してbFGF含有微細針3枚を圧挺貼布、3分間同部位に維持した後に除去してハイドロコロイド被覆材で被覆した。治療後は3日目からは遮光クリームの外用のみで経過観察した。治療直後から皺が浅くなるとともに皮膚の肌理の改善効果が認められ、治療後3月目に左外眼角部の皺(いわゆるカラスの足跡)はほぼ消失し、bFGF含有微細針の効果は極めて高かった(図7A、B、C)。
61歳、女性。左手背に対してbFGF含有微細針8枚を圧挺貼布、3分間同部位に維持した後に除去してハイドロコロイド被覆材で被覆した。bFGF含有微細針貼布直後に認められた紅斑は4-5日で消失、治療後は3日目からは遮光クリームの外用のみで経過観察した。治療後1ヶ月目にさらに同部位の周辺にbFGF含有微細針7枚を貼布した。その後、皮膚の肌理の改善効果が認められ、治療後3月目には突出し手いた静脈が平坦化、萎縮していた皮膚も厚さが回復され、bFGF含有微細針の効果は極めて高かった(図8A、B、C)。色素沈着などの有害事象は観察されなかった。
63歳、男性。右手背に対してbFGF含有微細針10枚を圧挺貼布、3分間同部位に維持した後に除去してハイドロコロイド被覆材で被覆した。bFGF含有微細針貼布直後に認められた紅斑は本症例では5日でほぼ消失、治療後は3日目からは遮光クリームの外用のみで経過観察した。治療直後から皮膚の肌理の改善効果が認められ、治療後3月目には突出し手いた静脈が平坦化、萎縮していた皮膚も厚さが回復され、bFGF含有微細針の効果は極めて高かった(図9A、B、C)。本症例でも色素沈着などの有害事象は観察されなかった。
24歳女性。右上梓の多発ケロイド。右肘部のケロイドに対してbFGF含有微細針10枚を圧挺貼布、3分間同部位に維持した後に除去してハイドロコロイド被覆材で被覆した。治療後に同部のかゆみ痛みなどの自覚症状が治療直後から改善し、治療後3ヶ月目にはケロイドが平坦化し、効果が明らかであった(図10A、B、C)。
(衝突力を印加する突刺試験)
直径1.5センチメートルの円形内に深さ約500マイクロメートル、開口部直径約300マイクロメートルの逆円錐状細孔225個を有するシリコン樹脂製のメス型を準備した。また、コンドロイチン硫酸ナトリウム100mgに精製水300マイクロリットルを加えて粘調性濃厚液を調製した。この粘調性濃厚液をメス型の穴の上に塗布し、約3.0MPaの加圧下でスキジーにて挿入した後、卓上遠心分離器を用いてメス型ごと回転させ、遠心力を利用して加重下、充填した。乾燥後、コンドロイチン硫酸ナトリウム100mgに精製水300マイクロリットルを加えて調製した粘調性濃厚液をメス型上に塗布した。単発打錠器の臼に錠剤用酢酸セルロースを入れ、約10kNの打錠圧で作成した直径1.5cm、厚さ約2mmの円形の錠剤基盤をこれに被せ、乾燥、硬化させた。その後、基盤をメス型から剥がして、目的物質を含まない刺入試験用微細針集積型製剤を得た。この刺入試験用微細針集積型製剤の皮膚に接触する側の面(前面)の面積は1.77cm2である。
(in vitro 2次的加圧試験)
参考例1と同様にして刺入試験用微細針集積型製剤を製造し、衝突圧21.3Nにて、in vitroで微細針をラットおよびヒトの皮膚に刺入した。その後、引き続いて微細針集積型製剤の背面を加圧した(2次的加圧)。その際、圧力及び加圧時間を変化させて、微細針の刺入深度がどのように変化するかを測定した。その結果を図12に示す。
(in vivo 2次的加圧試験)
参考例1と同様にして刺入試験用微細針集積型製剤を製造し、衝突圧21.3Nにて、ペントバルビタール麻酔下、ラットの腹部除毛皮膚に微細針集積型製剤を衝突させ、in vivoで微細針をラットの皮膚に刺入した。その後、引き続いて微細針集積型製剤の背面を加圧した(2次的加圧)。その際、圧力及び加圧時間を変化させて、微細針の刺入深度がどのように変化するかを測定した。その結果を図13に示す。
直径1.5センチメートルの円形内に深さ約500マイクロメートル、開口部直径約300マイクロメートルの逆円錐状細孔225個を有するシリコン樹脂製のメス型を準備した。また、インスリン10mg、エバンスブルー0.2mgおよびコンドロイチン硫酸ナトリウム10mgを秤量した後、70および75マイクロリットルの脱気精製水を各々加えて、粘調性の濃厚液をそれぞれ調製した。この粘調性濃厚液をメス型の穴の上に塗布し、約3.0MPaの加圧下でスキジーにて挿入した後、卓上遠心分離器を用いてメス型ごと回転させ、遠心力を利用して加重下、充填した。乾燥後、コンドロイチン硫酸ナトリウム440mgに精製水400マイクロリットルを加えて作成した粘調性濃厚液をメス型上に塗布した。単発打錠器の臼に錠剤用酢酸セルロースを入れ、約10kNの打錠圧で作成した直径約1.5cm、厚さ約2mmの錠剤基盤をこれに被せ、乾燥・硬化した。その後、基盤をメス型から剥がして、目的物質としてインスリンを含有する微細針を有する微細針集積型製剤2種を得た。
2…微細針、
21…第1部分、
22…第2部分、
3…先端部、
4…底部、
5…境界面。
Claims (14)
- 支持体と、該支持体上に複数形成された、体内溶解性かつ曳糸性の高分子物質からなる基剤及び当該基剤に保持された目的物質を有する円錐状又は角錐状の微細針とを、有する皮膚治療用微細針集積型製剤であって、
該目的物質が皮膚老化の予防又は治療、又は皮膚瘢痕の治療のために有効な物質である、
皮膚治療用微細針集積型製剤。 - 前記微細針は、先端部を有し目的物質を含む第1部分と、底部を有し目的物質を含まない第2部分とを、有する請求項1に記載の皮膚治療用微細針集積型製剤。
- 前記第1部分は、該皮膚治療用微細針集積型製剤の投与時に体内に挿入される微細針の長さ以下の挿入方向長さを有する、請求項1又は2に記載の皮膚治療用微細針集積型製剤。
- 前記第1部分は、該皮膚治療用微細針集積型製剤の投与時に真皮層内に挿入される微細針の長さ以下の挿入方向長さを有する、請求項1~3のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 前記基剤を構成する物質が、コンドロイチン硫酸及びその塩類、デキストラン、ヒアルロン酸及びその塩類からなる群から選択される少なくとも一種を含む請求項1~4のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 前記目的物質が、皮膚の細胞に作用する各種の増殖因子及び該増殖因子を皮膚の細胞が産生することを促進する物質からなる群から選択される少なくとも一種である請求項1~5のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 前記目的物質が、塩基性線維芽細胞増殖因子(bFGF)、酸性線維芽細胞増殖因子(aFGF)、それらの遺伝子をコードする核酸及びプラスミドからなる群から選択される少なくとも一種である請求項1~5のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 予防又は治療の対象になる症状が、皮膚の老化、紫外線障害皮膚、肥厚性瘢痕、萎縮瘢痕、ケロイド、ざそう瘢痕、脱毛、縫合創、熱傷創、潰瘍、褥瘡、糖尿病性潰瘍又は血管新生を必要とする疾患である請求項1~7のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 目的物質の含有量が、1パッチあたり0.01μg~1.0mgである請求項1~8のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 衝撃力が印加されて、微細針が皮膚に刺入される請求項1~9のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 前記衝撃力は、1.77cm2あたり5~40Nの衝突圧により印加されるものである請求項10に記載の皮膚治療用微細針集積型製剤。
- 衝撃力が印加されて、微細針が皮膚に刺入され、その後、2次的加圧が行われて、微細針が皮膚に刺入される請求項1~11のいずれか一項に記載の皮膚治療用微細針集積型製剤。
- 前記2次的圧力が1.77cm2あたり0.5~2.5Nである請求項12に記載の皮膚治療用微細針集積型製剤。
- 皮膚老化の予防又は治療、又は皮膚瘢痕の治療の対象である患部に請求項1~13のいずれか一項に記載の皮膚治療用微細針集積型製剤の微細針側の面を当て、所定の圧力を印加して、微細針を皮膚から体内へ刺入させる工程を包含する、皮膚老化の予防又は治療、又は皮膚瘢痕の治療のために有効な物質の投与方法。
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JPWO2015136639A1 (ja) * | 2014-03-12 | 2017-04-06 | 株式会社バイオセレンタック | 真皮内目的物質留置用マイクロニードル製剤投与部材及びマイクロニードル製剤迅速投与器具 |
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KR20180082177A (ko) * | 2017-01-10 | 2018-07-18 | 주식회사 아미코스메틱 | 사카로미세스 효모발효여과물, 아스파라거스줄기 추출물 및 관동꽃 추출물을 포함하는 화장료 조성물 |
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CN113521309A (zh) * | 2020-04-16 | 2021-10-22 | 中国人民解放军军事科学院军事医学研究院 | 人肝细胞生长因子基因在湿疹治疗中的应用及微针药械 |
CN113521309B (zh) * | 2020-04-16 | 2023-07-07 | 中国人民解放军军事科学院军事医学研究院 | 人肝细胞生长因子基因在湿疹治疗中的应用及微针药械 |
Also Published As
Publication number | Publication date |
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JPWO2013002331A1 (ja) | 2015-02-23 |
KR101881609B1 (ko) | 2018-07-24 |
BR112013033803A2 (pt) | 2017-02-14 |
EP2641614B1 (en) | 2020-12-30 |
CA2795995A1 (en) | 2012-12-28 |
DK2641614T3 (da) | 2021-03-29 |
CA2795995C (en) | 2020-03-24 |
EP2641614A4 (en) | 2015-11-04 |
US9795774B2 (en) | 2017-10-24 |
JP5977675B2 (ja) | 2016-08-24 |
AU2012247089B2 (en) | 2015-04-09 |
EP2641614A1 (en) | 2013-09-25 |
US20130072902A1 (en) | 2013-03-21 |
AU2012247089A1 (en) | 2013-01-17 |
TW201309351A (zh) | 2013-03-01 |
KR20140048024A (ko) | 2014-04-23 |
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