CN112807290A

CN112807290A - Novel scopolamine transdermal drug delivery patch

Info

Publication number: CN112807290A
Application number: CN201911040903.1A
Authority: CN
Inventors: 全丹毅
Original assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Current assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Priority date: 2019-10-30
Filing date: 2019-10-30
Publication date: 2021-05-18

Abstract

The invention relates to a scopolamine transdermal drug delivery patch for treating motion sickness, belonging to the technical field of medicaments. A transdermal scopolamine delivery patch comprises a scopolamine-containing reservoir layer, a backing layer, a pressure sensitive adhesive layer and an anti-adhesion layer; the method is characterized in that: the backing layer material comprises a PET/EVA composite material, a HDPE/EAA/nylon/EAA multilayer film material and an acrylic copolymer; the acrylic copolymer is a copolymer formed by crosslinking 73-77 wt% of acrylonitrile, 23-27 wt% of methacrylate and 8-10 wt% of butadiene/acrylonitrile; wherein the scopolamine reservoir layer and the like are sufficiently transparent visible skin surface layers.

Description

Novel scopolamine transdermal drug delivery patch

Technical Field

The invention relates to a scopolamine transdermal drug delivery patch for treating motion sickness, belonging to the technical field of medicaments.

Background

A tropane alkaloid with molecular formula of C₁₇H₂₁NO₄. The effects of the drug are similar to those of atropine, the mydriasis and glandular secretion inhibition effects of the drug are stronger than those of the atropine, the drug has an excitation effect on respiratory centers, but has an obvious inhibition effect on cerebral cortex, and the drug also has the effects of expanding capillaries, improving microcirculation, resisting carsickness and the like.

Most transdermal drug delivery patches of the prior art use impermeable backings to reduce the loss of pharmaceutically active ingredient. To increase user satisfaction, these backing layers are typically colored to a color similar to skin tone. However, providing a backing layer for a transdermal patch approximating all skin colors is difficult to commercialize.

Another approach that has been taken is to provide a transparent transdermal patch in which all of the components forming the patch are sufficiently transparent to allow the natural skin color to be seen through the patch. The commercial products adopting the method comprise ALORA and CLIMA estrogen substituted patches and DURAGESIC transdermal fentanyl delivery patches. When these formulations are applied to the skin, the patient's natural skin tone is visible, thus making the patch less visible. Government regulations dictate that these products must carry identifiable indicia, but that the indicia may be printed on these patches with a light or white ink, which is not visible for distances as long as a few meters, but is still visible after careful inspection.

The transparent patch is currently effectively applied to drugs with good stability, such as fentanyl and hormone replacement steroids, but is not applied to scopolamine drugs.

Scopolamine is a liquid alkaloid, is colorless, volatile, strongly alkaline, easily oxidized and unstable in illumination; scopolamine can penetrate not only human skin, but also many materials used in transdermal products such as polymers from which backings and packaging are made. Thus, the backing layer of currently available transdermal scopolamine delivery patches utilizes an opaque skin colored multilayer film, which typically comprises a metallized layer, such as aluminum.

Not only do commercial transdermal scopolamine patches use an opaque backing, but many of these patches also have other opaque ingredients due to the complexity of handling and processing scopolamine. For example, the original transdermal scopolamine product used a drug reservoir in the form of an opaque white gel, which was held in place by an opaque adhesive cover. The scopolamine patch is provided with an absorption pad in a drug container for absorbing scopolamine.

It has been proposed in the us patent to co-administer scopolamine with other drugs that improve the treatment of withdrawal from scopolamine.

Disclosure of Invention

The present invention relates to transparent transdermal scopolamine delivery patches, alone or in combination with other agents.

Such a patch is sufficiently transparent to allow the skin of the user to be seen through the patch. Patches printed with light colored or white ink are not easily found in close proximity, but can be found after careful examination.

The invention adopts a transparent polymer film as a back lining layer, and the permeability of the transparent polymer film to scopolamine is less than 1 mu g/cm²The optimal permeability of scopolamine is 0.5 mu g/cm²H; the solubility to scopolamine is less than 1% wt, wherein the optimal solubility is 0.1% wt. The film thickness is less than 0.15mm, wherein the optimal film thickness is 0.15 mm-0.10 mm. Such films are used in conjunction with one or more components of a transdermal patch (other than a removable release liner), such as a drug reservoir, adhesive, and rate controlling membrane, which are sufficiently transparent to allow visualization of the skin. The transparency index of the finished patch should be >55%, preferably > 65%, more preferably > 85%.

The backing layer should be transparent and sufficiently impermeable to scopolamine, yet must have sufficient mechanical strength and physical integrity to maintain the patch intact throughout the intended dosing period (typically 18-24 hours), and must provide stability to the adjacent layers of the interface, such as the drug reservoir or adhesive layer of the transdermal patch. One or more combinations of materials may be used and, thus, the transparent backing layer used in the patch of the present invention may be a multilayer film. In addition to low permeability to scopolamine, the backing layer must also have low solubility to scopolamine. This is because scopolamine is toxic, for example, licking the liner may pose a danger to children if the backing layer contains a significant amount of dissolved scopolamine.

The polymer materials used in the present invention include: SCOTCHPAK 1220 films of polyethylene terephthalate/ethylene vinyl acetate (PET/EVA), the two layer laminate films sold by the 3M company of Minneapolis, Minn, and SARANEX 2057 films of Dow chemical company of Midland, Mich, USA are High Density Polyethylene (HDPE)/Ethylene Acrylic Acid (EAA)/nylon/EAA multilayer laminate films. The crosslinked copolymer film material of nitrile rubber, acrylonitrile and methyl acrylate can also be used, and the market sales name is Barex @.

These films are formed from a crosslinked copolymer of about 73-77% acrylonitrile and about 23-27% methyl acrylate copolymerized at about 8-10% by weight of a butadiene/acrylonitrile copolymer; the butadiene/acrylonitrile copolymer containing about 70% by weight of polymer units derived from butadiene is a preferred backing material.

The transparent transdermal delivery patch of the present invention may be in any of the forms described in the above patents. However, a preferred form includes a backing layer and a scopolamine reservoir layer; the reservoir layer comprises scopolamine dissolved in the carrier at a concentration lower than the saturation concentration of scopolamine in the carrier. If the drug reservoir component is self-adhesive, a simple one-piece patch may be used. However, in many cases, it is desirable to add a tacky component to the rate controlling membrane to maintain the separate adhesive layer of the device. For all of these patches, the release layer is typically on the adhesive surface of the patch used to hold the patch on the skin, and is removed prior to use.

Various materials suitable for use in the present invention are known in the art and are disclosed in the above-mentioned patents.

The adhesive component uses pressure sensitive adhesives including, but not limited to, polysiloxanes, polyacrylates, polyurethanes, acrylic adhesives including crosslinked or uncrosslinked acrylic copolymers, vinyl acetate adhesives, ethylene vinyl acetate copolymers, and natural or synthetic rubber and polyisobutylene adhesives including polybutadiene, polyisoprene, and mixtures and crosslinked copolymers thereof. The present invention may use one or more binders. Such as polyvinyl alcohol and polyvinyl pyrrolidone, which can be used to form a single layer delivery patch, e.g., scopolamine is dissolved in an adhesive to form a self-adhesive drug reservoir; the adhesive can also be applied to the surface of a non-adhesive reservoir in which scopolamine is dissolved to form a multi-layered patch. It has been investigated to place a rate controlling membrane between a non-tacky scopolamine reservoir and an adhesive to achieve a controlled release effect.

Scopolamine can be combined with other drugs including anxiolytics, antihypertensives, antidepressants and appetite suppressants, such as fluoxetine, caffeine, buspirone, phenylpropanolamine, clonidine, paroxetine, citalopram and sertraline.

The scopolamine in the patch is present in the reservoir in a less than saturated state (i.e., less than a unit activity), so the reservoir scopolamine is completely dissolved. If other agents are present in the patch, they are preferably present in a completely dissolved form, but may be present in an undissolved form, as long as the final product exhibits suitable transparency.

In the present invention, scopolamine and the drug combination are passed through the skin or other body surface at a therapeutically effective rate for a predetermined period of time, with the predetermined suitable period of time for scopolamine being 16 to 24 hours.

Transdermal therapeutic patches of the present invention are prepared in a manner known in the art, for example, as described in the transdermal patches of the patents previously listed herein.

Detailed description of the preferred embodiments

The following examples are provided to illustrate the practice of the invention and are not intended to limit the scope of the invention.

Example 1

Various commercially available transdermal patches were tested to determine their clarity and compared to the clear scopolamine patch prepared according to the present invention. Scopolamine patches PET/EVA (SCOTCHPAK 1220 film, 3M, Minnesota) or SARANEX ® film (Dow Chemical Company, Midland, Mich.) and SCOTCHPAK 1006 film backings can be used. Light transmission through the various patches was measured by MACBETH 1500/Plus color. Table 1 shows the transparency index results for different patches.

The MINITRAN nitroglycerin patches are clear from a distance of about 1 meter, and the FEMPATCH patches are not obvious. ALORA, CLIMARA and NICODERM patches are not attractive. Thus, the transparency index of the transdermal patch according to the invention should be >55%, preferably > 65%, more preferably > 85%.

The foregoing is a brief and clear description of the invention and embodiments, and modifications and substitutions are considered to be within the scope of the present invention. Such modifications and substitutions may be made without departing from the scope of the present invention.

Claims

1. A transdermal scopolamine delivery patch comprises a scopolamine-containing reservoir layer, a backing layer, a pressure sensitive adhesive layer and an anti-adhesion layer; the method is characterized in that: the backing layer material comprises a PET/EVA composite material, a HDPE/EAA/nylon/EAA multilayer film material and an acrylic copolymer; the acrylic copolymer is a copolymer formed by crosslinking 73-77 wt% of acrylonitrile, 23-27 wt% of methacrylate and 8-10 wt% of butadiene/acrylonitrile; wherein the scopolamine reservoir layer and the like are sufficiently transparent visible skin surface layers.

2. The patch of claim 1 wherein: said drug reservoir layer said drug may be mixed in a pressure sensitive adhesive to form a reservoir layer, said drug reservoir layer comprising one or more pressure sensitive adhesive materials; polysiloxane, polyacrylate, polyurethane, acrylate adhesive, vinyl acetate-ethylene copolymer, natural rubber or synthetic rubber, and one or more pressure-sensitive adhesives selected from them and their adhesive copolymers are used as pressure-sensitive adhesive material.

3. The patch of claim 1 wherein: one or more hydrophilic water-absorbing polymers are contained in the patch.

4. The patch of claim 1 wherein: the solubility of scopolamine in the backing layer is < 0.01% wt.

5. The patch of claim 1 wherein: the patch has a transparency index > 55%.

6. The patch of claim 1 wherein: the backing layer comprises a PET/EVA laminate film;

the patch of claim 1 wherein: the backing layer comprises a HDPE/EAA/nylon/EAA multilayer laminate film.

7. The patch of claim 1 wherein: the backing layer material is composed of 73-77 wt% of acrylonitrile, 23-27 wt% of methacrylate and 8-10 wt% of butadiene/acrylonitrile cross-linked copolymer.

8. The butadiene/acrylonitrile cross-linked copolymer had a butadiene content of 70 wt%.

9. The patch of claim 1 wherein: the scopolamine in the patch can release medicine for 16-24 h continuously.

10. A transdermal scopolamine delivery patch is characterized in that: the backing layer material comprises a PET/EVA composite material, a HDPE/EAA/nylon/EAA multilayer film material and an acrylic copolymer; the acrylic copolymer is a copolymer formed by crosslinking 73-77 wt% of acrylonitrile, 23-27 wt% of methacrylate and 8-10 wt% of butadiene/acrylonitrile; wherein the scopolamine reservoir layer has a transparency index of > 55%.