JPH0226602B2 - - Google Patents

Description

[Detailed description of the invention]

BACKGROUND OF THE INVENTION In recent years, various drug release systems have been developed that can be inserted subcutaneously to enable sustained release therapy. Systems have also been published that provide drug release systems suitable for transdermal drug administration. US Pat. No. 3,964,106 discloses a microseal drug release device suitable for implantation or transdermal use as well as intravaginal or intrauterine use. The present invention provides that when nitroglycerin is released, the triglyceride of saturated coconut acid, i.e. Migroyl oil 812 or palmitic acid isopropyl ester, alone or in combination with mineral oil, is added to the hydrophilic solvent system in the polymer matrix.
It was discovered and completed that drug transport is significantly enhanced and drug release is increased. U.S. Pat. No. 3,996,934 consists of a backing and a facing portion having at least one reservoir containing a systemically active drug, either as a separate layer or as a plurality of microcapsules distributed throughout the silicone polymer matrix. A medical bandage is also disclosed. Nitroglycerin powder is shown as an example. British patent application BG2021950 discloses nitroglycerin bandages containing 1 to 10 parts of nitroglycerin per 100 parts of carrier. Mineral oil and lanolin are stated to enhance the transport and absorption of nitroglycerin when the carrier is selected from the group consisting of polyethylene, polypropylene, polybutylene and polymethylbutylene. Despite such prior art teachings, currently available topical nitroglycerin dosage forms are only ointments or creams that not only stain the skin but also It must be applied more frequently and over a much larger area. SUMMARY OF THE INVENTION The present invention relates to a transdermal delivery system for the administration of nitroglycerin, and more particularly provides a pad of nitroglycerin that can be easily applied to the skin and allows for the administration of nitroglycerin transdermally over an extended period of time. It is. The size of the pad of the present invention can be varied depending on the dosage requirements of each patient. The preferred size is 2 x 4 cm. The pad of the present invention is comprised of a biologically compatible silicone polymer matrix having microseal chambers throughout the microseal chambers containing nitroglycerin in a hydrophilic solvent system and containing nitroglycerin and biological The ratio of the partition coefficient of a compatible silicone polymer matrix to the solubility of nitroglycerin in a hydrophilic solvent system is between 1 and 10 ^-4 ml/mcg.
It is. A hydrophobic solvent system is also added to enhance the diffusion of nitroglycerin through the matrix. The nitroglycerin is preferably dispersed in the matrix as a nitroglycerin-lactose mixture for ease of handling and safety.
When it comes into contact with the skin, a therapeutically effective amount is diffused through the biocompatible silicone polymer matrix. The pad is designed so that the liquid on its surface triggers the initial contact of the pad with the skin, promoting diffusion and absorption from the pad to the skin. The materials used to form the biocompatible polymeric container are those that form a thin wall or membrane through which the drug can pass at a constant rate. A suitable polymer is biologically and pharmaceutically compatible, non-allergenic, insoluble and non-irritating to the body fluids or tissues with which it comes into contact. The use of soluble polymers should be avoided since dissolution or corrosion of the device will affect the rate of drug release and at the same time cause the device to move from its original position making removal inconvenient. Examples of materials for forming biocompatible polymeric containers include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, and silicone. Rubber, especially medical polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride; vinyl chloride and vinyl acetate,
Polymethacrylic acid ester polymer (hydrogel), vinylidene chloride, copolymer with ethylene and propylene; polyethylene terephthalate,
Examples include butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymer, ethylene/vinyloxyethanol copolymer, and the like. For best results, the biologically compatible polymeric container should be selected from polymers of the types described above and having a glass transition temperature below room temperature. The polymer may have some degree of crystallinity at room temperature, but this is not necessary. Preferred biologically compatible silicone polymer matrix materials are room temperature or high temperature crosslinked silicone rubbers (polydimethylsiloxanes), e.g. (wherein R is _C1 - _C7 alkoxy, vinyl or allyl, and n is about 100-5000). Suitable polymers are capable of forming a thin wall or film through which nitroglycerin passes at a constant rate, are biologically and pharmaceutically compatible, are non-allergenic, are insoluble and non-irritating to the skin. and preferably has the following parameters.

Table: Hydrophilic solvent systems that can be used in the practice of this invention are generally about 10-30% by volume solutions of polyethylene glycol, preferably polyethylene glycol 400, in distilled water. This hydrophilic solvent system is embedded in a silicon matrix along with a hydrophobic solvent system.
The complex solvent system introduced within this matrix serves the unique purpose of dispersing the nitroglycerin throughout the matrix and enhancing diffusion, allowing for a constant rate of delivery of nitroglycerin once the pad is applied to the skin. . The nitroglycerin is diffused into the skin through the pad and absorbed to exert the desired pharmaceutical effect. The hydrophobic solvent system is comprised of about 5-15% by weight of a compound or mixture thereof selected from the group consisting of palmitic acid isopropyl ester, mineral oil, cholesterol or triglycerides of saturated coconut oil, such as migliol oil. The addition of palmitic acid isopropyl ester alone or in combination with, for example, mineral oil or cholesterol improves the transport and absorption of nitroglycerin. Prior to manufacturing the pads of the invention, a commercially available 10% nitroglycerin-lactose mixture of 6 to 60% was added to the hydrophilic solvent system.
Preferably, 22% by weight is added. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS A preferred embodiment of the present invention comprises a backing that does not absorb or transport nitroglycerin, a silicone polymer matrix affixed to the backing;
Its silicone polymer matrix is formed by crosslinking silicone rubber in situ.
A cross-linked silicone rubber with microseal cells of 10 to 200 microns, mixed with a hydrophilic solvent system containing nitroglycerin and a hydrophobic solvent system that enhances the transport and diffusion of nitroglycerin;
When this microsealed pad of nitroglycerin is applied to the skin, the nitroglycerin diffuses through its biocompatible silicone polymer matrix at a therapeutically effective constant rate while the hydrophilic solvent Microsealed nitroglycerin pad for transdermal administration that does not diffuse within a biocompatible polymer matrix. A particularly preferred embodiment of the present invention is the formula (In the formula, R is alkoxy, alkyl, phenyl,
vinyl or allyl, and n is about 100 to 5000); The polymer matrix has microseal cells distributed throughout the microseal cells containing water; 10-30% by volume of polyethylene glycol; and a hydrophobic solvent selected from oils derived from mineral oil, coconut oil, or its like. mixture 5-15
10% by weight nitroglycerin-lactose mixture in a hydrophilic solvent consisting of 6-22% by weight.
Microseal cells are formed by emulsifying a liquid silicone polymer with a hydrophilic solvent containing nitroglycerin and a hydrophobic solvent and then crosslinking it in situ. In preparing the nitroglycerin pads of the present invention for transdermal administration, the nitroglycerin pads of the present invention are generally prepared in a suitable hydrophilic solvent system, such as a 10-30% (V/V)% polyethylene glycol 400 solution in distilled water. % nitroglycerin-lactose mixture is prepared.
During this preparation, an excess amount of the nitroglycerin-lactose mixture is added and stirred by hand or machine for about 5 to 10 minutes to maintain a homogeneous paste.
Apply this uniform paste to silicone elastomer,
For example, MDX4−4210 elastomer (Dow
Corning Midland Michigan) along with the required amount of a hydrophobic solvent or solvent mixture, such as mineral oil, palmitic acid isopropyl ester, or mixtures thereof. All of these ingredients are mixed for 5 to 15 minutes in a low shear, explosion resistant mixer maintained at a vacuum of 45 to 70 cm. Add the polymerization catalyst and continue mixing under reduced pressure for approximately 15-30 minutes. The final mixture is viscous and poured onto a clean, dry stainless steel plate using a mixing device. For 2 x 4 cm pads, pour the appropriate amount of the final mixture onto a 12" stainless steel plate with a frame of desired thickness, ranging from 5.0 mm to 1.2 mm. Pour a suitable material such as aluminum foil. Place the top plate over the substrate so that the top plate has the same dimensions as the bottom.Alternatively, you can fill the mold by pressing the polymerization mixture into the mold without using a frame. is held in place and placed in a convection oven at approximately 60°C. After 2 hours, the mold is removed, allowed to cool, and the crosslinked pad material adhering to the aluminum foil is pulled out.
Cut to a suitable size, for example 2 x 4 cm, along with an aluminum foil backing. The pads are then stored in a closed container. The pad preferably contains from about 6% to about 22% by weight of a commercially available 10% nitroglycerin-lactose mixture, which provides optimal transdermal dosage. The optimal dosage was determined by a series of bioavailability experiments on pure nitroglycerin and pads of the invention at different doses and thicknesses, as described in the Examples below. Next, the present invention will be explained in more detail with reference to the following examples. Example 1 10% nitroglycerin-lactose mixture (55g) labeled with ^C14 nitroglycerin at 10% (V/V)
Polyethylene glycol 400 deionized water solution 25.0
g for about 5 minutes. A homogeneous paste of this mixture was applied to 157.5 g of MDX4-4210 silicone elastomer (Dow Corning, Midland, Michigan).
added to. Initial mixing for about 10 minutes with no air provided a homogeneous dispersion in a low shear mixer. 12.5 g of MDX4-4210 elastomer crosslinker was added to the dispersion and mixing continued for an additional 15 minutes. The final mixture was poured into 12" x 12" stainless steel plates with a 5 cm frame to hold the crosslinking material. Place aluminum foil (12" x 12") on each plate and place a 12" x 12" stainless steel The mold was pressed into a steel plate mold.The mold was held by screws on the four corners and placed in a convection oven for 2 hours at approximately 60°C.After cooling, the polymer matrix with aluminum foil as a backing was removed from the mold. It was taken out, cut into 1.6 x ^3.2 cm pads, and stored in a sealed container until use.
V) Deionized water solution of polyethylene glycol 8
g for about 5 minutes. A homogeneous paste of these ingredients and 20 grams of mineral oil were mixed into 45 grams of MDX4-4210 silicone elastomer. First mixed for 10 minutes to remove air and obtain a uniform dispersion with a low shear mixer. 5 g of crosslinking agent was added to this mixture, and mixing was continued for about 15 minutes with the air removed. Add the final mixture to 5 mm
Poured into a stainless steel plate with a thick frame.
Place a 12″ x 12″ piece of aluminum foil on top;
The upper plate of the mold was placed on top of it, pressed, and fixed with screws provided at the four corners. Place the mold in a convection oven at 60°C for approximately 2
heated for an hour. After cooling, the polymer matrix adhering to the aluminum foil backing was removed from the mold, cut into 1.6 x 3.2 cm pads, and stored in a closed container until use. Example 3 10% nitroglycerin-lactose labeled with ^C14 -nitroglycerin 11 g, 10% (V/V) polyethylene glycol 400 in deionized water 4.0 g, MDX
Nitroglycerin pads (1.6 x 1.6 cm) were prepared according to the method of Example 2 from 27.5 g of -4-4210 silicone elastomer, 5.0 g of palmitic acid isopropyl ester and 2.5 g of crosslinking agent. The pads were stored in a sealed container until use. Example 4 C ¹⁴ -labeled nitroglycerin - lactose 22g, 10%
(V/V) Polyethylene glycol 400-deionized aqueous solution 8.0g, Miglyol 812 oil 20.0g, MDX4-
A 2 x 4 cm nitroglycerine pad was prepared according to the method of Example 2 from 45.0 g of 4210 silicone elastomer and crosslinker. The pads were stored in a sealed container until use. Example 5 11 g of C ¹⁴ -labeled nitroglycerin-lactose mixture,
Nitroglycerin powder (2 x 4 cm) was prepared according to the method of Example 2 from 7 g of a 10% (V/V) polyethylene glycol 400 solution in deionized water.
A mixture of a homogeneous paste of the above ingredients, 13.0 g of palmitic acid isopropyl ester and 6.0 g of mineral oil was added to 57 g of MDX4-4210 silicone elastomer, and after the first stirring, 6.0 g of crosslinking agent was added and the following procedure was carried out as in Example 2. . The pads were stored in an airtight container until use. Example 6 C ¹⁴ -labeled 10% nitroglycerin - 11 g of lactose,
10% (V/V) polyethylene glycol 400 4g deionized water, palmitic acid isopropyl ester
Nitroglycerine powder (2 x 4 cm) was prepared according to the method of Example 2 from 5.0 g of mineral oil, 22.5 g of MDX4-4210 silicone elastomer and 2.5 g of crosslinker. The pads were stored in an airtight container until use. Example 7 ^C14 -labeled 10% nitroglycerin-lactose mixture
5.5 g, polyethylene glycol 400 deionized water solution 4.0 g, palmitic acid isopropyl ester 7.5
2.times.4 and 1.6.times.1.6 cm nitroglycerin pads were prepared according to the method of Example 2 from 5.0 g of mineral oil, 25.5 g of MDX4-4210 silicone elastomer, and 2.5 g of crosslinker. The pads were stored in a sealed container until use. Example 8 ^{3 g} of C14-labeled nitroglycerin in a 10% nitroglycerin-lactose mixture, 2.25 g of 10% (V/V) polyethylene glycol 400 in deionized water, 5.0 g of palmitic acid isopropyl ester, 5.0 g of mineral oil.
A 2.times.4 cm pad was prepared according to the method of Example 2 from 31.5 g. of MDX4-4210 silicone elastomer (Dow Corning, Midland, Michigan) and 3.25 g. The pads were stored in a sealed container until use. Example 9 3 ^g of C14-labeled nitroglycerin in a 10% nitroglycerin-lactose mixture, 2.5 g of 10% (V/V) polyethylene glycol 400 in deionized water, 7.5 g of palmitic acid isopropyl ester, 5.0 g of mineral oil.
g, MDX4-4210 silicone elastomer 29.5g
and 2.75 g of crosslinking agent, 2×4 cm nitroglycerin powder was prepared according to the method of Example 2. The pads were stored in a sealed container until use. Example 10 The topical availability of nitroglycerin was investigated in vivo using Lusus monkeys (Macaca mulata). It has been shown for many compounds that dermal absorption in this animal model is similar to that in humans. Animals were placed on a metabolic chair throughout the dosing study. Urine was collected while the animal was placed in the metabolic chair. Once the pads were removed, the animals were released into metabolic cages, but urine collection continued. ¹⁴ C-labeled nitroglycerin was applied to the skin.
Although it can be applied anywhere on the body surface, for convenience, the ventral side of the forearm or the upper part of the inner forearm was used. The area of the application part is generally small, about 2 to 10 ^cm2 , but any area can be used. The final concentration is expressed as a quantity per unit area of skin (i.e.
1.0mg/ ^1cm2 ). For liquids, creams or ointments, the dose was spread precisely over the skin area. In the case of the pad of the invention, it was attached to the skin with tape. For liquids, creams or ointments, the treated area was covered with aluminum foil and taped. In each case, the tape, foil and nitroglycerin pad were removed after 24 hours, and the application site was wiped three times with ethanol-soaked gauze and then washed with soap and water. Absorption was determined based on the percentage of radioactivity excreted in the urine for 3 days after application of a known amount of labeled nitroglycerin to the skin. The daily urinary excretion amount was corrected by the following formula based on the excretion and retention of radioactivity from other routes when labeled C ¹⁴ -nitroglycerin was administered intravenously. Absorption rate = % dose of urinary radioactivity during local administration / % dose of urinary radioactivity during intravenous administration × 100 ^C14 by the nitroglycerin powder of the present invention
- In the case of labeled nitroglycerin powders, the residual radioactivity was analyzed after the device was removed from the skin. The amount of radioactivity dissipated from the device was determined to be released in vivo during application to the skin by quantification of the amount of radioactivity lost from the device compared to the case of the device not applied to the skin. Radioactivity measurements were performed using a commercially available liquid scintillation counter. To measure the amount of radioactivity in this study, 1.0 ml of radioactive urine was added to a scintillation solution (PCS solubilizer, Amersham
Corporation, Arlington Heights, Illinois, 10
ml). Radioactivity in urine mixed with scintillant was counted using a liquid scintillation counter to quantify the amount of radioactivity. The absorption of pure nitroglycerin is shown in Table 1.
This data indicates that the local concentration of nitroglycerin is 0.1
When increasing from 1.0 mg/ ^cm2 skin area, the bioavailability of nitroglycerin during 24-hour application remains at a constant value, indicating that it is more than 40%.
Local concentrations of 7 and 10 mg/ ^cm2 show decreased absorption, with the maximum optimal dose of 5 mg/cm2 providing good bioavailability.
It was concluded that cm ² .

TABLE Nitroglycerin release and bioavailability data from nitroglycerin for transdermal administration prepared according to the method of Examples 1-9 are shown in Table 2.
In Table 2, nitroglycerin powder for transdermal administration is
MDD-NG, nitroglycerin is abbreviated as NG. From literature data for topical nitroglycerin ointment, an effective clinical response to nitroglycerin of approximately 20 to 40
mg (Cardiology: 63 ,
337, 1978; Amer. Heart J. 96 :578, 1978). Although the nitroglycerin powders in Examples 1 to 9 use ^C14 -labeled nitroglycerin for the purpose of bioavailability studies, it is natural that ordinary nitroglycerin powders are manufactured from unlabeled nitroglycerin. be. Also, as will be apparent to those skilled in the art, lactose mixtures are used for convenience and safety in handling.

【table】

[Table] Example 11 10% nitroglycerin-lactose mixture 275g
% (V/V) polyethylene glycol 400 in deionized water. A homogeneous paste of these ingredients, palmitic acid isopropyl ester
325.0g, mineral oil 150.0g, MDX4-4210 crosslinking agent
150g MDX4-4210 silicone elastomer
Added to 1425.0g. The mixture was mixed in a Helicone 4CV mixer (Atlantic Research Corporation,
Gainesville, VA) for 5 minutes without removing air, then continued mixing under 60-70 cm vacuum for 30 minutes. Appropriate amount (100-140g) of the final mixture, 1.3
Poured into a 12″ x 12″ stainless steel plate with a mm frame. A piece of aluminum foil was placed on top of the poured material in each plate and pressed into the mold with a 12″ x 12″ plate. Secure the mold with screws at the four corners and place in a convection oven for 60 minutes.
It was left at ℃ for 2 hours. After cooling, the crosslinked polymer matrix adhering to the aluminum foil was removed from the mold, covered with aluminum foil overnight, and stored.
The pads were cut into 2 x 4″ pads approximately 2 mm thick. These pads were coated with SURLYN laminate foil (Ludlow
Co., Lombard, Illinois) and stored in a suitable container.

Claims (1)

Claims: 1. A backing comprising a biologically compatible silicone polymer matrix affixed to the backing, the silicone polymer matrix having a
It is a cross-linked silicone rubber with multiple ~200 micron micro-seal cells inside, and the cells contain about 6-22% by weight of a mixture of 10% nitroglycerin in lactose, mineral oil, palmitic acid isopropyl ester, saturated Contains 10 to 30 parts by volume of an aqueous hydrophilic solvent system containing 5 to 15% by weight of a hydrophobic solvent system selected from the group consisting of triglycerides of coconut oil acid and mixtures thereof, the hydrophilic solvent system being polyethylene glycol. , a microsealed nitroglycerin pad suitable for transdermal administration of nitroglycerin. 2 Hydrophilic solvent system is polyethylene glycol 400
The pad of nitroglycerin according to claim 1, which is an aqueous solution of. 3. The nitroglycerin pad according to claim 2, wherein the hydrophobic solvent is palmitic acid isopropyl ester. 4 Claim 2 in which the hydrophobic solvent is mineral oil
Nitroglycerin powder as described in section. 5. The nitroglycerin pad according to claim 2, wherein the hydrophobic solvent comprises palmitic acid isopropyl ester and mineral oil. 6. The nitroglycerin pad according to claim 2, wherein the hydrophobic solvent is mineral oil and miglyol oil.