System for transcutaneous administration of nicotine(85)18.06.2001

FIELD: pharmaceutical industry.

SUBSTANCE: invention is characterized by that system contains underlayer, therapeutical substance storage layer, and agent attaching the system on the person's skin and allowing access of nicotine to skin. System is transparent (opacity factor below 48.6%).

EFFECT: facilitated transcutaneous transport of nicotine.

8 cl, 1 tbl

 

This invention relates to percutaneous delivering devices for administration of nicotine used in the treatment to stop Smoking. In particular, the invention relates to a device for percutaneous delivery of nicotine, which are transparent.

The level of technology

Percutaneous method of parenteral drug delivery has many advantages relative to other routes of administration. Percutaneous delivery of a wide range of drugs and other beneficial agents are described in U.S. patents№3598122, 3598123, 3731683,3797494, 4031894, 4144317, 4201211, 4286592, 4314557, 4379454, 4435180,4559222, 4568343, 4573995, 4588580, 4645502, 4698062, 4704282, 4725272, 4781924, 4788062, 4816258, 4849226, 4904475, 4908027, 4917895, 4938759, 4943435, 5004610, 5071656, 5122382, 5141750, 5284660, 5314694, 5342623, 5411740 and 5635203, the contents of which are fully incorporated in the description by reference.

It was shown that the introduction of nicotine hominids (through the mucous membrane of the mouth), nasal and dermal to help the patient who wants to stop Smoking, is clinically effective in reducing the relapse rate. Nicotine chewing gum and nicotine for percutaneous introduction represent two of the most widely used forms of nicotine-replacement therapy currently available. Percutaneous device for the introduction of nicotine are described, for example, in U.S. patent No. 4597061, 4758434 4764382, 4839174, 4908213, 4915950, 4943435, 4946853, 5004610, 5016652, 5077104, 5230896, 5411739, 5462745, 5508038, 5599554, 5603947 and 5726190, the contents of which are fully incorporated in the description by reference.

In most known devices for percutaneous drug delivery using an impervious substrate, located on the far relative to the skin side of the device to protect the device from damage and prevent the loss of active ingredient(s). In order to better meet the needs of consumers, these substrate layers often give a color close to skin tones. However, it is easy to understand that the creation of colored layers of a substrate for systems percutaneous action, suitable for all colors of skin, is not a sustainable solution for mass production.

Another approach, which was adopted, is the establishment of transparent systems for percutaneous action, in which all elements forming the device are sufficiently transparent, allowing the natural color of the skin was visible through the device. Existing products on the market that have implemented this approach include estrogen replacement patch Alora®, Climara® and system for percutaneous delivery of fentanyl Duragesic®. When these devices are attached to the skin, the natural skin color of the patient is visible through the patch, making the presence of the patch, highly unobtrusive. Normal the main documents required to supply these products identifying data, but such data can be printed on the specified device or bright white paint that is invisible at the distance of several feet (over one meter), but readable when viewed at close range.

Data transparent patches have been shown to be effective when used with non-volatile medicinal substances such as fentanyl and hormone replacement steroids, but to deliver nicotine was not developed any clear product.

Nicotine is a liquid alkaloid, which is a colourless, volatile, highly alkaline, easily oxidized, prone to decomposition when exposed to light and a well penetrating not only through human skin, but also through many polymers commonly used for the production of layers of the substrate and packaging materials for products percutaneous actions (see, for example, U.S. patent No. 5077104). As a result, layers of the substrate device for percutaneous delivery of nicotine, currently available, use an opaque multilayer film color, which usually contain a metallic layer such as aluminum layer.

In addition, commercially available nicotine patches percutaneous actions are opaque substrate, many such devices due to the difficulty of treatment with nicotine and it is processing other components, which are opaque. For example, in the original nicotine product Prostep® percutaneous steps were used tank for medicinal substance in the form of an opaque white gel, which is fixed with opaque adhesive coating layer. The nicotine patch Habitrol®, Nicotrol® in the tank for medicinal substance placed absorbent filler impregnated with nicotine.

It was also suggested that the introduction of nicotine together with other substances that improve the treatment goal of abstinence from Smoking. Examples of such solutions are disclosed, for example, in the above-mentioned patent No. 4908213, 5599554 and 5726190 and publications WO 97/33581.

The invention

This invention relates to transparent systems (devices) percutaneous delivery for percutaneous administration of nicotine as monocomponent or in combination with other agents.

Such devices should be sufficiently transparent so that the skin of the subject could be clearly seen through the device placed on the skin. Identifying information may be printed on the device light or white paint so that they are invisible at a short distance, but readable at close quarters.

According to this invention, the system (device) for percutaneous administration of nicotine contains a substrate layer, a layer of a reservoir of the drug substance, supported by the substrate layer, and a means of retention on the skin of the subject with the possibility of admission to the skin of nicotine.

Preferably, the execution layer of the substrate from a material selected from the group consisting of laminated plastics polyethylene terephthalate/ethylene copolymer and vinyl acetate, the multilayer plastic of high density polyethylene /ethylenically acid/nylon/ethylenically acid and films containing grafted copolymer derived from about 73-77% Acrylonitrile, and about 23-27% of methyl acrylate, copolymerizing in the presence of about 8-10 parts by weight of a butadiene/Acrylonitrile copolymer containing about 70 wt.% the polymer of the monomers butadiene.

Preferably, if the substrate has a permeability to nicotine, less than about 1.0 mg/cm2h, more preferably less than 0.5 g/cm2PM

In one embodiment, the substrate has a solubility in the nicotine less than about 1 wt.%, in another embodiment less than about 0.1 wt.%.

Preferably, if the system has a coefficient of opacity less than about 48,6%, more preferably less than 35,11% and most preferably less than 20%.

Information confirming the possibility of carrying out the invention

In preferred embodiments of the proposed system (device) is as a layer of the substrate using a transparent polymer film, which has a permeability to nicotine less than 1 µg/cm2h, preferably less than 0.5 ág/cm2h and solubility in nicotine less than 1 wt.%, preferably less than 0.1%. The thickness of such film is preferably less than about 6 mils (152,4 μm), comprising in the preferred case of about 2-4 mils (50,8-101,6 mm). Such films are used in combination with one or more conventional elements of the device for percutaneous delivery (non-removable protective film), such as a reservoir of medicinal substance, sticky membrane and membrane regulation of the speed of release, which must also be sufficiently transparent so that the natural color of the skin was clearly visible through the assembled device after it is put on the skin. The final product should have a coefficient of opacity less than about 48.6 per cent, preferably less than about 35,11% and more preferably less than 20%.

In addition to transparency and sufficient impermeable to nicotine layer of the substrate must also have sufficient mechanical strength and physical integrity to maintain the system in an intact condition within the stipulated period of introduction, which is usually 18-24 hours, and must form a stable contact with the surface of adjacent layers, such as a reservoir Le is artenova substance or adhesive layers of the device, percutaneous injection. One material does not always have such a combination of properties and is therefore transparent substrate layers used in the device corresponding to the invention may be a multilayer film. In addition to low permeability for nicotine layer of the substrate should have a low solubility in nicotine. This is because nicotine is toxic and child could be dangerous, for example, to lick the substrate layer, if it contained a significant amount of dissolved nicotine.

Suitable polymeric materials having the properties required for the present invention include Scotchpak® 1220, which is a polyethylene terephthalate/ethylene copolymer and vinyl acetate (PET/EVA) double - layer film supplied by ZM, Minneapolis, Minnesota, and Saranex® 2057, which is a multilayer plastic (multilaminate)consisting of high density polyethylene (HDPE)/ethylenically acid (EAK)/nylon/EAK supplied by DowChemical company, Midland, Michigan. Can also be used grafted copolymers of nitrile rubber with Acrylonitrile and methyl acrylate, available on the market in the form of a film Wagah®, described in U.S. patent No. 5077104.

These films containing grafted copolymer derived from about 73-77% Acrylonitrile, and about 23-27% bromide is relata, copolymerizing in the presence of about 8-10 parts by weight of copolymers of butadiene/Acrylonitrile containing about 70% by weight of polymer monomers derived from butadiene, are the preferred materials for the substrate.

Transparent device for percutaneous delivery, corresponding to this invention, can be performed in any of the forms described in the aforementioned patents. However, in the preferred embodiment, the device has a layered structure comprising a substrate layer, a supporting layer tank medicinal substances (tank nicotine), which contains nicotine, dissolved in medium at a concentration below the saturation concentration of nicotine in the media. If the component reservoir of medicinal substance is self-adhesive, you could use a simple monolithic device. However, in many cases, it is desirable to include additional components, such as membranes speed control is released and the tool holding device on the skin with the possibility of admission to the skin of nicotine, for example a separate adhesive layer for holding the device on the skin, as described in the above mentioned U.S. patent No. 5004610 and 5342623. Next, we mean that in addition to nicotine, the device may also contain other medicinal washes the VA or other active substance, which operate together with nicotine or enhance the effects of nicotine in Smoking cessation, the replacement area or substitution therapy area. In all such devices on the sticky surface of the patch, which is used for holding the device on the skin, usually impose a removable protective film which is removed before use of the device.

Various materials suitable for the manufacture of various components known in the field of technology and described in the aforementioned patents.

Sticky component is preferably adhesive, bonding with pressure, including without limitation polysiloxanes, polyacrylates, polyurethanes, acrylic adhesives, including cross-stitched or unstitched acrylic copolymers, adhesives based on vinyl acetate, ethylenevinylacetate copolymers and natural or synthetic rubbers, including polybutadienes, polyisoprenes and polyisobutylene adhesives, as well as their mixtures and graft copolymers. The device may also contain known hydrophilic water-absorbing polymers, such as polyvinyl alcohol and polyvinylpyrrolidone, used separately or in combination with each other. Glue can be used for the manufacture of monolithic delivering device, in which nicotine is dissolved in the adhesive with the formation of camogliese the Osia reservoir of medicinal substance. In another embodiment, the adhesive may be applied onto the non-sticky surface of the tank in which the dissolved nicotine, with the formation of a multilayer device. Between reservoir for nicotine and glue can be placed membrane regulation of the speed of release, as is known in the prior art.

Nicotine can be introduced in combination with other agents, which can include antianxiolytic, antihypertensive drugs, antidepressants and drugs to reduce appetite, such as fluoxetine, caffeine, buspirone, phenylpropanolamine, clonidine, paroxetine, citalopram and sertraline.

The nicotine in the device is in the reservoir in the state of abasement (slightly undersaturated solution), i.e. below the units of activity, so in the tank there is no undissolved nicotine. If the device is equipped with other agents, they are preferably present in completely dissolved form, but may be present in non-dissolved form, as long as the final product has the proper degree of transparency.

In this invention the nicotine and optionally other agents designed for use with introduction, are delivered through the skin or other body surface with a therapeutically effective rate over a specified period of time, for which nicotine is preferably 16-24 hours.

<> Therapeutic percutaneous device actions, corresponding to this invention, is made known in the technical field, such as by the methods described in the above mentioned patents relating to devices percutaneous procedure.

The following example serves to illustrate the practical implementation of the present invention and should not be considered as limiting the invention in any way.

Example 1

Various commercially available plasters for percutaneous steps were tested to determine their transparency and compared with clear nicotine patches, relevant to this invention. These nicotine patches were made as described in example IV of U.S. patent No. 5004610 with the replacement of the substrate Scotchpak 1006 substrate PET EVA (Scotchpak® 1220, 3M Company, Minneapolis, Minnesota) or substrate Saranex®(Dow Chemical Company, Midland, Michigan). Light passing through different systems was measured using the system for color measurement Macbeth 1500/Plus (Kollmorgen Instruments Corp., Newburgh, new York). Table 1 gives the results of measurements of the coefficient of opacity, which is the percentage of incident light absorbed when passing through the device for different investigated systems.

Table 1

Indicators opacity patches

PatchThe coefficient of opacity
Minitran®48,6%
Alora®20,21%
FemPatch®35,11 %
Climara®19,33%
Example 1 -The nicotine pad and Saranex®17,04%
Example 1 -Nicotine with a substrate of PET/EVA19,66%

Nitroglycerine system Minitran® is well visible from a distance of about 5 feet (1.5 m), while FemPatch® is significantly less noticeable. However, the patch Alora®, Climara® and Nicoderm® are highly unobtrusive. Accordingly, device, percutaneous steps, corresponding to this invention, should have a coefficient of opacity less than 48,6%, preferably less than 35,11%, more preferably less than 20%.

Thus, after describing the essence of the present invention and its preferred embodiments it is clear that various modifications and substitutions will be obvious to a person skilled in the art. Such modifications and substitutions can be made within the scope of the present invention, to the E. is limited only by the following claims.

1. System for percutaneous administration of nicotine containing layer of the substrate, the layer of the tank medicinal substances that are supported by the substrate layer, and a means of retention on the skin of the subject with the possibility of admission to the skin of nicotine, characterized in that the substrate layer is made of a material selected from the group consisting of laminated plastics polyethylene terephthalate/ethylene copolymer and vinyl acetate, the multilayer plastic of high density polyethylene/ethylenically acid/nylon/ethylenically acid and films containing grafted copolymer derived from about 73-77% Acrylonitrile, and about 23-27% of methyl acrylate, copolymerizing in the presence of about 8-10 parts butadiene/Acrylonitrile copolymers containing about 70 wt.% the polymer of the monomers butadiene, the system is transparent and provides visibility into the skin of the subject when placing on it.

2. The system according to claim 1, characterized in that the substrate has a permeability to nicotine less than about 1.0 µg/(cm2h).

3. The system according to claim 1, characterized in that the substrate has a permeability to nicotine less than 0.5 ág/(cm2h).

4. The system according to claim 2, characterized in that the substrate has a solubility in the nicotine less than about 1 wt.%.

5. The system according to claim 3, characterized in that the substrate has Rast is almost in the nicotine less than about 0.1 wt.%.

6. The system according to claim 4, characterized in that it has a coefficient of opacity less than about 48.6 per cent.

7. The system according to claim 6, characterized in that it has a coefficient of opacity less than 35,11%.

8. The system according to claim 6, characterized in that it has a coefficient of opacity less than 20%.

The priority according to claims 1,2-5, 16.03.1999 according to claims 1,6-8, 18.12.1998.



 

Same patents:

The invention relates to medicine, namely to ophthalmology, surgery, etc

The invention relates to medicine, namely to ophthalmology, surgery, etc
The invention relates to the field of medicine and relates to means for the prevention and treatment of caries, hyperesthesia, remineralization of hard tissues of teeth
The invention relates to medicine, in particular for experimental medicine
The invention relates to medicine, specifically to Oncology, and can be used in clinical practice Oncology hospitals

The invention relates to the field of dentistry and refers to funds that have a stimulating effect on the processes of cell renewal

The invention relates to medicine, to compositions containing polar lipid composition on the basis of nicotine in liquid crystals and colloidal dispersions and their predecessors or secondary products, which are in contact with fluid body and/or under the influence of body temperature into liquid crystals, or a mixture of liquid crystals, which acts as a matrix with controlled release of nicotine, suitable for Smoking cessation and/or replacement area

The invention relates to medicine, namely to addiction
The invention relates to medicine, namely to urology, andrology, and can be used in the treatment of infertility in men

FIELD: pharmaceutical industry.

SUBSTANCE: invention is characterized by that system contains underlayer, therapeutical substance storage layer, and agent attaching the system on the person's skin and allowing access of nicotine to skin. System is transparent (opacity factor below 48.6%).

EFFECT: facilitated transcutaneous transport of nicotine.

8 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves recording arterial blood pressure, heart beat rate, respiration frequency, sublingual body temperature and rectal body temperature. The measurements are repeated 3, 5, 7, 9, 11, 13, 15, 20 min later after introducing xanthinol niacinate. Difference of maximum and minimum values of each factor is calculated, respectively. Parasympathetic patient responses predominance is determined from calculated values.

EFFECT: high accuracy in determining organism tolerance to reactive vasoconstriction.

2 cl, 4 tbl

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention relates to nicotine-containing preparations possessing prolonged stimulating effect and used in loss the smoking habit. The preparation is prepared by a method involving preparing a gel-base by addition of 2.5-3.0% gel of hydroxypropylcellulose in ethanol to 10-13% ethanol solution of copolymer of N-vinylpyrrolidone with organic unsaturated acid ester in the mass ratio copolymer of N-vinylpyrrolidone with organic unsaturated acid ester : hydroxypropylcellulose in gel-base = (7.0-1):(7.5-1). Then cetyl alcohol, isopropyl myristate, propylene glycol, preliminary melted stearic acid, colloidal silicon dioxide and nicotine are added successively to the prepared gel-base at constant stirring and temperature 30-35°C. Invention provides enhancing the prolonged effect of the preparation.

EFFECT: improved preparing method, enhanced and valuable properties of preparation.

3 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves delivering nicotine to patient organism and administering medicament by smearing internal surface of superior and inferior nasal passage part. Treatment is carried out with cigarette consumption being retained. Smell receptor canal blocker like rapid sodium canal blocker lidocaine is used as the medicament. Its aerosol is introduced immediately before smoking action as single jet in each nasal passage. Medicament introduction is localized with epithelial smell receptor cells arrangement.

EFFECT: enhanced effectiveness of treatment.

2 cl, 2 tbl

Up!