DE2922792A1 - MEANS FOR TOPICAL ADMINISTRATION OF NITROGLYCERIN - Google Patents

Description

PATENT LAWYERS

WUESTHOFF-v. PECHMAlN N -BEHRENS-GOETZ

PROFESSIONAL REPRESENTATIVES BEFORE THE EUROPEAN PATENT OFFICE MANDATAIKES AGREES PRES!. 'OFFICE EUROPEEN DES BREVETS

TkOKF v7 2

DR.-ING. FRANZ DR. PHIL. FREDA WUESTHOFF (1927-1956) DIPL.-ING. GERHARD PULS (1952-1971) DIPL.-CHEM. DR. E. BARBER OF PECHMANN DR.-ING. DIETER BEHRENS DIPL.-ING.J DIPL.-WIRTSCH.-ING. RUPERT GOETZ

D-8000 MUNICH SCHWEIGERSTRASSE phone: (089) 66 20 ji telegram: protectpatent telex: j24070

IA-52 31

Patent application

Applicant:

RIKER LABORATORIES, INC. 19901 Nordhof! Street, Northridge, California 91324 USA

Title:

Means for topical administration of nitroglycerin

909849/0942

PATENT LAWYERS

WUESTHOFF - ν. PECHMANN - BEHRENS - G0ET2

professional representatives before the european patent office agrees pres l'office europeen des brevets

Often.-ING. VKaNZ ' DR. PHIL. FREDA VUESTHOFF (1927-I956)

l) tPL.-INU. GERHARD PULS (1952-I971)

DIPL.-CHEM. DR. E. BARBER OF PECHMANN DR.-ING. DIETER BEHRENS DIPL.-ING .; DIPL.-XTIRTSCH.-ING. RUPERT GOETZ

D-8000 MUNICH SCHWEIGERSTRASSE 2 phone : (089) 66 20 ji TELEGRAM: PROTECTPATENT TELEX: J 24 070

Note: Riker Lab. 1A-52316

description

The invention relates to the administration of Nitroglycerin to the circulatory system. In particular, it relates to the topical administration of a therapeutic one Amount of an agent containing nitroglycerin with the aid of bandages or plasters and agents suitable therefor or preparations. The invention also relates to carriers for nitroglycerin which are suitable for the preparation of the Preparations and processes for the manufacture of the preparations and carriers.

Although the preparations according to the invention can be used with the plasters and bandages, this is not the case required and the preparations cannot only be used in connection with these associations. Similar can the carrier can also be used for the production of preparations other than those according to the invention.

However, the invention relates in any case to the transfer of nitroglycerin (often abbreviated as NTG) to the Circulatory system through the skin.

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There are various preparations for administration of the drug known. A common method is sublingual administration (where a tablet is taken from the Medicines dissolved in the mouth, preferably under the tongue will), although this form of administration results in a relatively short duration of action, generally of up to 30 minutes, which means that repeated administration of tablets may be necessary.

NTG formulations for topical administration (in which the drug is delivered through the skin to the circulatory system) are also known and have been used for many years. For example, an ointment containing 2 % NTG is usually applied to the skin and the area is covered with a tight-fitting (occlusive) layer such as a saran or polyethylene cover, which is held in place by an adhesive tape. Despite the inconvenience of topical administration, it has the important advantage of a longer duration of action compared to sublingual administration generally up to 3 to 4 hours, with a maximum duration of action of 6 hours reported in one case (WR Taylor et al, Am. J. Cardiol.,? _8f 469 (1976).

The amount of ointment, the total dose of NTG and the area the skin on which the ointment is applied vary according to the state of the art within wide limits. Thus, from doses of 5 to 60 mg NTG and application areas reported from 14 to 464 cm '". In the clinical literature however, the most effective clinical doses are indicated to be in the range of 30 to -200 µg / cm NTG.

It is already known to use NTG in a more convenient way To be used in dosage form for topical administration, e.g. in the form of an (adhesive) tape or strip. In the US PS

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5,996,934; specified a bandage that is used to continuously deliver drugs to the skin at a controlled rate. The dressing comprises a backing, a reservoir which contains the drug to be administered (as a layer of the dressing or as a plurality of microcapsules distributed in a matrix) and a membrane that controls the delivery rate, which is connected to the surface of the reservoir is laminated. A dressing for topical administration of NTG at a controlled rate is indicated in which approximately 0.9 % NTG is contained in hardened silicone rubber (the NTG is contained in microcapsules which are distributed in the rubber). However, no data are given for this with regard to the rate of release or duration of action.

Thus, the state of the art with regard to the topical administration of NTG is characterized by numerous variations (e.g. in the amount of ointment applied, the concentration of NTG in the ointment, the treated skin area, the various ways of measuring the amount of NTG available to the skin, etc.), with a view to a delivery system to: achieve that is able to deliver effective amounts for treatment over prolonged periods of time while simultaneously it is avoided that too large a quantity of NTG is available at the beginning, which can lead to negative and even dangerous results Side effects leads. Although a system that is capable of a relatively constant, reproducible and adjustable To deliver therapeutically effective amount of NTG over a period of 8 to 24 hours or more is very desirable would (which would mean an increase in convenience and freedom for the patient, as well as for the Care of Patients), no such delivery system has been developed to date. The procedure and the associations according to the invention are particularly suitable for such a

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term longer delivery time.

Before it is possible to use NTG for pharmaceutical purposes, however, it is first necessary to danger ·? to get rid of. Commercially available formulations for topical administration of IJTG use lactose as an inert Carrier and petrolatum-lanolin mixtures as vehicles. Lactose is a particularly beneficial carrier as it is different favorable properties united. For example, it is non-toxic, relatively cheap, and readily available and in combination with IJTG not sensitive to impact.

Certain preparations that contain NTG lactose own however, the disadvantage that they leave behind an unpleasant snow-white solid residue (if the preparation is absorbed into the skin), which is detrimental for topical applications. Furthermore, the currently available NTG lactose preparations further limitations and disadvantages. E.g. they are generally oily and greasy, with the result that they look uncomfortable and an uncomfortable one

result from feeling and are often e.g. / a cover from Saran or polyethylene covered to stain and Avoid contaminating clothes, bed linen, etc.

If one wants to overcome the residue problem, it is necessary to inert the lactose with another To replace carrier. This leads to numerous problems and Ms has not yet been reached. 'Finding one alternative pharmaceutically acceptable NTG carrier (which must be safe and stable, no disturbing residue and must have the other beneficial properties of lactose) is difficult and physical in itself dangerous. And even if a promising alternative carrier has been found, further attempts are necessary

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be carried out carefully, as the stability and security in the presence of the alternative carrier and different Adjuvants can lead to additional problems. The carriers according to the invention which are inert towards NTG do not leave any visible residue, are safe to use and have the other benefits of lactose as mentioned above are. They consist of a polymer powder suitable for the production of an ointment, with nitroglycerin on the Particles in an amount of about 1 to 20 parts of nitroglycerin per 100 parts of the total carrier is adsorbed. The polymeric powder suitable for the production of an ointment consists preferably of polyethylene, polypropylene, polybutylene and polymethylbutylene. Polyethylene is particularly preferred. The carriers preferably contain 1 to 10 parts of nitroglycerin to 100 parts of the entire carrier.

The carriers are prepared by mixing a solution (preferably a no more than 20 ⁽ ; 6igen solution) containing 1 to 20 parts of nitroglycerin in a suitable volatile solvent therefor, such as a lower alkanol, e.g. methanol, ethanol, a ketone, e.g. acetone, a Ether, e.g. diethyl ether, a hydrocarbon, e.g. pentane, among others, with a slurry of 99 to 80 parts of a polymeric »powder suitable for the preparation of an ointment in the same ο de r / (Ia ^- Im" c compatible volatile solvent (the slurry preferably contains at least 50 % solvent), the sum of the proportions of nitroglycerin and the powder being 100. The solvent (s) is then evaporated off, the nitroglycerin remaining adsorbed on the pp ^ - mer particles for the solution as well as the slurry, is acetone.

* (Ointment forming)

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The invention also relates to a group of pharmaceutical preparations which are suitable for topical use Administration, and Methods of Making Carriers and Preparations.

The preparations according to the invention include the new ones NTG carriers contained in certain newly developed, non-greasy occlusive devices. These preparations are easy to manufacture from the new NTG inert carriers and are safe and stable. They are also not oily or greasy and leave no unwanted residue. As a result, it is not necessary to use the relevant Cover the area to protect clothes and / or bedding from soiling.

With the help of the medical bandages according to the invention it is possible to continuously deliver NTG to the circulatory system released by transmission through the skin. The associations consist of

(1) a backing that represents a surface of the dressing, and

(2) a drug supply that includes the. IiTG together with contains a "\ feHkel, which is used for the passage of the NTG is permeable,

the drug supply being adapted to be kept in direct contact with the skin (when the bandage is applied) and a substantially constant rate of absorption of NTG through the skin (to the Circulatory system) for at least 8 hours. So it seems, as will be explained later, that in absentia an intermediate layer which determines the speed, the skin itself determines the speed of absorption Factor serves. Other elements associated with the association, such as "ax Arxeuesvehikäs and the completion of the drug supply however, have an influence on the speed

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which the skin absorbs the NTG.

The dressings according to the invention thus represent at least an important advance over what "could be achieved according to the state of the art: a therapeutic treatment with NTG at an essentially constant rate during normal sleep (8 hours). The constant rate preferably maintains, however, at least 10 hours on and for certain forms of administration longer times for the constant administration rate are desirable. For example, a constant rate of dispensing over 16 hours would allow the patient to put the bandage on before dressing in the morning and not think about it until He undresses 16 hours later A delivery rate constant over 24 hours would allow the patient to take care of it only once a day (at the most convenient time) and longer constant delivery times such as 48 hours would be desirable for the patient topical NTG administration to non-ambulatory patients, For example, hospital and home care will be facilitated '. A significant amount of time is often required for qualified nurses to frequently use the products currently available on the market. The use of dressings according to the invention significantly reduces the time required for application, and the longer dispensing significantly reduces the required frequency of application, both of which lead to considerable time savings. In addition, the invention results in greater accuracy and uniformity of application, predictable drug response, _and greatly facilitates the monitoring and treatment of patients. Furthermore, the cosmetic advantages of the bandage or plaster according to the invention (ie the ease of use, the non-soiling, etc.) lead to an easier application

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for outpatients who need this medication. Dressings with a substantially constant rate of release (zero order) over the above-mentioned time periods are possible and preferred according to the invention.

In addition to the pad for the drug supply, the bandages preferably also comprise a non-irritating, pressure-sensitive one Adhesive that surrounds the supply for the drug on the outside. The pressure sensitive adhesive is like this designed to keep the drug supply in direct contact with the skin. The drug supply is preferred separated from the pressure-sensitive adhesive by an intermediate layer which is both opposite to the drug as well as being inert to the adhesive and which serves to separate these two components from one another (E.g. about a migration of the NTG into the adhesive, a smear of the drug supply over the adhesive etc. to avoid). In addition, contain the invention Dressings desirably have a protective layer that covers the drug supply before the * dressing is applied. the Protective layer can also cover the pressure sensitive adhesive, or this can be covered by a separate protective layer covered, thereby making it possible to separately reveal the adhesive and the drug.

1 shows a plan view of a bandage according to the invention and FIG. 2 shows a perspective view. In these figures, the drug supply 10, the intermediate layer of an inert material 11 and the pressure-sensitive adhesive 12 are indicated. J Further, the pad 13 and the protective layer 14 in Fig. 2 are shown ~ D ± e invention also relates to a method for topical Verabrei monitoring a therapeutic amount WTG, at the certain on an area of skin a medicament stock containing HTG together with egg

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A vehicle that is permeable to the passage of the NTG is applied, the drug supply being formed in this way is that it delivers a substantially constant amount of NTG through the skin over at least about 8 hours. Usually, concentrations of approximately 1000 to 4000 / Ug NTG / cm are used in the dressings according to the invention applied. The bandages are applied to special areas of the skin and the therapeutically effective contents NTG in the blood are maintained as long as the supply of NTG remains large enough to essentially absorb the to maintain a constant rate of absorption. Usually the rate of absorption for the NTG to the bloodstream during this time no less than about 20 / Ug / cm skin χ hour.

It is believed that the transition of the NTG from the surface of the skin to the circulatory system is roughly as follows expires: the skin to which the drug itself is applied (or especially the stratum corneum, which is seen as a rate-determining factor) essentially acts like a diffusion membrane. The rate of diffusion thus depends on the type or condition of the skin, as well as factors such as the type the intermediate layer between the drug supply and the skin (and is determined, among other things, by the type of drug used for the Drug supply affects the vehicle used, as will be seen later), from the drug supply is tightly covered or not, etc. For a given type of application, however, these factors are proportionate constant and the diffusion rate is proportional to the difference between the concentrations of NTG the outside and inside of the skin.

Since NTG is quickly transported away from the inside of the skin, there is no significant concentration Medicines under the

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Skin (ie the concentration of the drug on the inside of the skin is approaching zero). In order to maintain a relatively high concentration of ITTG on the outside of the skin, it is necessary that the diffusion of the active ingredient through the skin is faster than the diffusion through the skin (membrane) and this appears to be the case when a suitable medium for the ITTG is selected. A supply or reservoir of HTG must also be available to replace the ITTG that has passed through the membrane and to maintain the IITG content at or near the critical range (e.g. the saturation content of M ¹ G in the vehicle) obtained in order to keep the rate of passage constant or almost constant over a longer period of time within practical limits. It appears that this can be achieved by a suitable content of the drug supply of, for example, lactose or a suitable polyolefin such as polyethylene containing up to 10 % ITTG (fSWhr NTG is presumably released by dissolution mechanisms when the NTG in the surrounding vehicle decreases). Since the rate of metabolism of NTG to ineffective products is significantly greater than the rate of topical infusion. such a delivery system leads to a constant drug content in the circulatory system and a state of equilibrium is quickly reached. By appropriately adjusting the total amount of NTG that is applied and the surface area to which it is applied (e.g. the size of the drug supply and the volume of the dressing), this state of equilibrium can be set so that a uniform therapeutic amount of active ingredient over a long period of time Period is given.

Different patterns that occur when the type of administration from NTG to the skin can be explained with this hypothesis, as can be seen from the examples.

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going on. So a larger reservoir of NTG only has one little effect on the initial rate of absorption of NTG but maintains a linear rate of absorption upright for long periods of time. Covering (e.g. with Saran) the one with a lower amount of NTG-containing Ointment treated area (as is typical in the prior art) leads to a higher initial Absorption rate than without this cover, however, has no significant influence on the time-duration and the amount delivered. Although the composition of the agent containing the NTG (e.g. in high concentration) influences the rate of delivery of the NTG to the circuit, the rate of delivery remains for a certain one Administration form generally constant until the reservoir of NTG is exhausted to such an extent that the concentration drops well below a certain critical value in the vehicle.

Although it is not essential, it is usually preferred that the vehicle no more than about 4 wt -.% NTG contains, at least where it comes into contact with the skin. The reason for this is that skin irritation can occur if the skin is exposed to higher concentrations of NTG over a long period of time, and such higher concentrations are usually not necessary in order to achieve the advantages according to the invention. Preferably the vehicle contains about 2 % NTG. Lower percentages of NTG can also be used, but in general there are no practical benefits when using concentrations less than about 1% NTG.

The advantages that can be achieved according to the invention can be conveniently are shown with the help of a widely used in-vitro diffusion rope model for skin penetration, using hairless mouse skin.

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In the special test method used here, hairless or naked mouse skin strain HRS / J, age 7 to 8 months, male (from Jackson laboratory) applied. It was frozen until 30 minutes before use held. The mouse skin was split in half and each half onto a cell of the type shown in FIG attached. The cell was arranged as indicated in the literature (e.g. J.L. Cohen, R.B. Stoughton, I. Invest. Derm., .. 62, 507 (1974) and R.B. Stoughton, Arch. Derm., 99, 753 (1964). As indicated in the figure, is the mouse skin with the epidermis (outer layer) facing up between the upper and lower part of the cell 21 and 22, which are held together with the aid of a clamp 23 (ball joint clamp). The cell will Filled under the skin with normal saline solution (10 ml of fresh 0.9% aqueous sodium chloride solution), which serves as the "acceptor" liquid. The side arm 25 is closed with a stopper, except when the solution is withdrawn will.

A known amount of the preparation to be tested is applied to the epidermis (upper side of the skin) as follows applied in an even layer; the desired amount of preparation plus a certain amount Any excess (due to mechanical losses) is precisely put together with a flexible applicator stick (a Piece of * Polyethylene tube heating over a colorful burner, "flattened" at one end with a spatula and cut smooth with a razor blade to obtain a smooth end) weighed out. the The preparation is applied to the skin that has already been attached in the diffusion cell and becomes even Layer spread out. The applicator is then weighed back with the remainder of the preparation still adhering to it. The difference between this weight and the original

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The weight corresponds to the amount applied to the skin of preparation.

The cell is then placed in a chamber with constant temperature (32 ^° C.), constant humidity (50 % relative humidity) and left there during the experiment. The chamber uses a heat exchanger connected to a constant temperature bath and a fan to circulate the air. A saturated calcium nitrate solution is used to maintain moisture. The acceptor liquid is stirred with the aid of a magnetic stirrer (24) for 60 s prior to taking samples in order to produce a uniform sample. At specific time intervals, portions (5.0 ml, half of the total volume) are withdrawn and fresh saline solution is added - in order to replace the withdrawn liquid immediately. The removed portions are examined for the NTG content according to the method of Bell (j.Pharm. Sei 53, 752 (1964) and the cumulative amount (total amount) of the NTG which has passed through the skin is calculated. The values for the cumulative NTG amount as a function of time gives a curve for the delivery of the drug.

Preparations or ointments that can be used for the bandages according to the invention or the method according to the invention include non-greasy ointment preparations or sarbene bases, petrolatum, petrolatum containing up to about 30 % or more lanolin, petrolatum containing wax (paraffin) and petrolatum containing lanolin and Paraffin together with the NTG. The latter is advantageously added as a mixture with lactose powder (lactose powder containing 10% NTG, which is not explosive and is commercially available, is particularly suitable). Lanolin has been shown to facilitate the passage of the NTG through the skin. This may be due to the surfactant effects of some of the ingredients in lanolin (e.g. sterols) that help NTG move through the skin. The wax is used to increase the melting point of the preparation and thereby possibly occurring

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to avoid adverse effects during handling and shipping (otherwise the occurrence of higher temperatures during shipping could lead to the preparation melting. The following preparations (A, B and C, each containing 2 ^c /!> NTG) are representative of preparations that can be applied according to the invention.

Λ. Laonolin Petrolatum Preparation. Lactose powder containing 10 % HTG is carefully mixed with the lanolin using a spatula on a glass plate. The mixture and petrolatum are then combined by vigorous mixing (also with a spatula on a glass plate) until homogeneous. Wax (paraffin) can be added by melting the desired amount of wax and petrolatum together on the steam bath while stirring until a homogeneous solution is formed and the mixture is cooled to room temperature before mixing with the lanolin-lactose powder-NTG mixture. A typical agent containing 10 % wax and 10 % lanolin has the following composition:

g weight yo

10 % NTG 2.0

on lactose 12.0 18.0

Lanolin 6.0 10.0

Paraffin 6.0 10.0

White petrolatum, U.S.P. 56.0 60.0

60.0 g 100.0 %

This preparation (preparation A, containing 10 % lanolin, 10 % wax and 2 % NTG) is preferred for the medical dressings according to the invention (island dressing delivery system).

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B. Preparation B contains 2 % NTG in a lanolin petrolatum vehicle ("Nitro-Bid" from Marion Laboratories, Inc. of Kansas City, Mol). A solid non-irritating ointment forming powder contain% - also suitable for the inventive preparations of the invention are associations that about 40 to 90 wt .-% of a fat viscous base substance and about 10 to 50 wt.. The viscous basic substance is selected from solid petrolatum, animal oils, mineral oils, synthetic oils, the oils being thickened with an agent selected from the group of waxes and hydrocarbon polymers. The ointment powder comprises a polyolefin having 2 to 6 carbon atoms in the repeating unit, "a molecular weight of about 3,000 to 150,000 and a mean maximum size of less than about 30 µm ⁰ C does not absorb the fat viscous basic substance is the viscous base substance is mixed with the above-mentioned ointment forming powder at a temperature of less than about 50 ⁰ C to the powder is nitroglycerine in an amount of about 0.5 to 4 wt... - %, based on the total preparation, absorbed.

The ointment-forming powder in the preparations is preferably polyethylene. It is preferred that the thickening agent is about 0.3 to 0.5 wt -.% Based on the viscous matrix of an amorphous, elastomeric, non-vulcanized block copolymer are used, the a middle of terminal styrene blocks having a glass transition temperature above 25 ° C and Molecular weight between about 2,000 and 100,000 and a central isoprene block with a glass transition temperature below that of the end blocks. Such a block copolymer is, for example, "Kraton" 1107 from Shell Chemical Company,

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These preparations are produced by a process which is essentially an extension of the process used for the production of the non-greasy occlusive agents as indicated in GB-PS 1,503. ,% Of a fat viscous base substance and about 10 to 60 wt .-% of a solid non-irritating, suitable for preparation of an ointment powder wherein said viscous - then the nitroglycerin-containing carrier is in this case added to a composition comprising about 40 to 90 wt. The base substance is selected from the group consisting of solid petrolatum, animal oils, mineral oils and synthetic oils, the oils having been thickened by an agent selected from the group consisting of waxes and hydrocarbon polymers and wherein the powder suitable for producing an ointment contains a polyolefin 2 to 6 carbon atoms in the repeating unit, a molecular weight of about 3,000 to 150,000 and a mean maximum particle size of less than about 30 µm. The viscous basic substance is absorbed by the non-ointment-forming powders below 50 ⁰ C and the fat substantially viscous · basic substance is mixed with the ointment forming powder at a temperature below about 50 C. The carrier containing the nitroglycerin is added as part of the ointment powder in such an amount that the total preparation contains approximately 0.5 to 4% by weight of nitroglycerin.

A non-greasy agent as used in accordance with the invention is prepared, for example, as follows: a styrene-isoprene-styrene block copolymer ("Kraton" 1107 Shell Oil Company), unscreened polyethylene powder, and light mineral oil (NS) are made by heating the ingredients mixed with stirring to 140 ° C. in a ratio of 1: 19.03: 168.67 to form a solution. This solution is left Solidify into a primary ointment by adding small amounts

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it is poured into a container which has been cooled in an ethanol-water ice bath to -15 ⁰ C and for ensures that the temperature does not exceed about O ⁰ C increases (ie, it must be rapidly cooled). Then 17.66 parts of propylene glycol USP and 50.15 parts of sieved polyethylene powder (this powder can also serve as an alternative as a carrier for the NTG, as described above and given in Example 7) are added to 100 parts of solidified primary ointment and the resulting product thoroughly mixed until the ointment appears homogeneous. The mixture is then passed through a grinder three times. An additional 5.26 parts of sieved polyethylene per 100 parts is added to this second milled ointment with thorough mixing.

The following composition is obtained with the given method:

Copolymer

Polyethylene (unscreened) light mineral oil (N.F.) Propylene Glycol (U.S.P.) Polyethylene (sieved) Total

C. A 2.0% NTG preparation in a non-fat Ointment is made by adding commercially available 10? 6 NTG lactose to this TfeHkeL by rubbing it on a glass plate with a spatula. A typical preparation is composed as follows:

G Weight % 12.0 0.30 228.4 5.71 2024.0 50.60 400.0 10.00 1335.6 33.39 4000.0 g 100.00

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Oik

g wt -.%

10 % NTG 2.0

on lactose 12.0 18.0

non-fatty ointment 48.0 80.0

Total 60.0 g 100.0 %

4 (which is discussed in more detail in connection with Example 1 shows the results that were achieved with the usual topical administration of NTG-containing ointments, compared with the use of the agents or preparations according to the invention. The results were obtained using the obtained in vitro model described above (test with hairless mouse skin). As can be seen from this curve, at an application rate of 192 / Ug NTG / cm (what for the known means is typical) a substantially constant delivery or. Flow rate of NTG (speed the transition from NTG to the acceptor solution) for approximately the first 3 to 4 "hours. Thereafter the speed of passage decreases rapidly (as can be seen from the flattening of the curve). With the larger dose, however, as is typical of the invention, the flow rate remains constant for approximately 24 hours.

The desired flow rate can be specified by taking the best straight line through the absorption curve with the help of an ointment containing the usual amount of NTG (192 ug / cm) for the first 2 to 4 hours / The ratio of the flow velocities (gradients in Fig. 4) for the usual means versus the application of a higher dose, determines the part of the range over which the usual ointment must be distributed, which is required in a higher dose in order to achieve the same overall penetration of the Drug per unit of time (and thus the

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same therapeutic effect over a longer period of time). In these procedures one should be "at an effective clinical dose." of 20 mg NTG in a 2% ointment (i.e. 1.0 g ointment) applied to a 100 cm area of skin, and a calculated dose of 128 mg NTG in a 2% SaI-be (i.e. 6.4 g of ointment) applied to an 80 cm area of skin, an identical flow rate over 24 hours, as with the lower dose over 4 hours. In any case, this corresponds to an amount of 1600 / Ug / cm.

As stated above, it is usually an application amount

2
of at least 1000 / Ug / cm NTG in the inventive mit-

/ 2

materials required and application rates of 4000 / ug / cm or above can be applied. The lower application rates are suitable when shorter application times and / or slower absorption rates are required (e.g. in a patient who has a constant, relatively low dose NTG only required for 8 hours of sleep). The larger quantities of NTG can be used be about a substantially constant flow rate of NTG in relatively high doses 24, 48 hours or even a few days. The concentration however, the NTG must not be so high that unpleasant skin irritation or other side effects occur.

The inventive method is preferably using a dressing of the invention carried out (as opposed to the simple application of an ointment from a tube directly onto the skin) _e The reason for this is a üsiditere controlling the _amount? a more even reaction, easier application ^ and aesthetic considerations? The bandage, preferably in the form of a plaster (island dressing), enables an even layer of the medicinal ointment and a reproducible surface

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area (and consequently an even or easily controllable delivery of NTG) from application to application. This is much more accurate than measuring a strand of ointment as it comes out of a tube.

The coverage and feeding are with a bandage fairly constant, which makes the effect maximum and the response more even.

The bandage can be put on more easily and quickly by the patient himself or by a helper (nurse) or are applied.

Finally, from the aesthetic point of view, the dressing is much more pleasant and the inconvenience becomes avoided associated with an ointment with a petrolatum.

Suitable pads or cushions for the bandages according to the invention include films or sheets or fabrics, the may be non-porous or microporous and / or macroporous, as indicated, inter alia, in US Pat. No. 3,214,501. In particular foils made of polyethylene, polypropylene, polyester, etc. metal foils (e.g. aluminum foils), polyurethane foam can be used -rfolien or textile materials made of ethylene-vinyl-acetate-copolymer or foils or nonwovens made of randomly oriented Ryon fibers can be used. Foams with a Open cell structures made of polyether, polyurethane and polyester are suitable matrices that contain the nitroglycerin in the preparation hold on and release from it. Metal foils alone or with a polymer base to increase strength Laminated, are preferred as a solid back as they do not blow, and do not change shape when warm and will not cause any plasticization, migration or other chemical interaction with the NTG, the pressure-sensitive ones Adhesives, carriers or other substances that are present.

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If the preparation as a layer on a 'foil or film-like base is applied, part of the preparation often adheres to the protective layer (which is usually to protect the surface of the drug supply) when it is removed. This problem essentially does not occur when matrix-like documents are used in which the drug preparation is held in the gaps between the base and not only on the top side (e.g. foams, Woven or non-woven fabrics). For this reason and because such pads are sufficiently porous that they allow migration Do not inhibit the drug on the skin, these materials are preferred.

If a non-porous or non-absorbent pad is used, the exact amount of drug formulation can be used (e.g. ointment) can be spread cold over the surface and then heated to form a smooth coating. Optionally, the preparation can be applied hot in a measured amount to the surface. If the underlay is porous, the preparation can be applied warm (so that it is absorbed by the base). A proportionate one thin porous base (like a foam) can be immersed in the liquefied hot preparation, to avoid the entrapment of air and to achieve a uniform shape for application.

The inert protective layer is conveniently made of a material with low adhesion, such as polyethylene coated paper made lubricious with silicone oil. Optionally, a semi-rigid thermoplastic cover may be used, which is shaped so that it gives an air space between the Wakel and the cover.

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The pressure-sensitive, ie pressure-sticking (self-lifting) adhesives used in the dressings according to the invention are essentially non-irritating to the skin and essentially do not react with the NTG preparation. Preferably they are. self-adhesive and sufficiently heat and lightfast to avoid the addition of tackifiers and stabilizers. Pressure-sensitive adhesives which are suitable for the bandages according to the invention are known and are given, for example, in US Pat. No. 3,769,971, in particular column 3, lines 38 to 52, column, line 35 to column 6, line 33, column 6, lines 40 to 52 and column 7 lines 13-17, U.S. Patent (RE) 24,906, and U.S. Patent 2,925,174, incorporated herein by reference. Preferred pressure-sensitive adhesives can be described, for example, as rubber-like, usually tacky adhesives of the acrylate and urethane type with a 100% modulus of less than 7 kg / cm, vo:
U.S. Patent Specified.

ρ ρ

than 7 kg / cm, preferably less than 5 kg / cm, as in Figs

The invention is illustrated in more detail by the following non-limiting examples. In all examples was the test with hairless mouse skin and the Beil method for examining the absorption fluid for NTG (as described above) applied.

example 1

Comparison of the absorption profiles of NTG over approximately 24 hours of samples with a state-of-the-art representative NTG content and samples as required for the present Invention (containing 8x more NTG).

Preparation B described above (2% NTG in one Lanolin petrolatum carrier) was applied to both samples and both samples were covered with saran (the saranab-

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2322792

coverage was on the skin after applying the ointment, however applied to the cell prior to attaching the glass lid (results are shown in Figure 4).

Samples 1 to 3 and samples 4 to 6 are repetitions of the same experiment. The surface area of the hairless mouse skin on which the ointment is in the diffusion cell

'2

was 1.75 cm. Samples of 5 ml of the saline solution were taken at the indicated times (and immediately replaced with fresh saline) and examined for the NTG concentration. From this concentration (, ug / ml NTG) was the total amount (cumulative amount) WTG, which had passed through the skin, calculated at each point in time and the percentage of the amount applied, the this corresponds, for sure. The following equations show the processing of the data obtained to make the cumulative percentage amount of NTG, based on the originally applied To calculate the amount at any point in time η.

i (/ Ug / ml NTG) _n χ 10 (ml) = (/ Ug NTG) _n

n-1

^. (/ Ug NTG).

ii (/ Ug NTG) _n + ^{1 = 1} ; = (Cum. / Ug NTG) _n

iü (Cum. / UgNTG) _n χ .100 _{= (Cum #}

(/ Ug ointment applied) χ, 02

(The second term on the left of equation ii gives the total amount of. NTG absorbed that prior to the Sampling ζ «Zt. η has been removed from the saline solution).

Table I below contains information relating to samples 1 to 3 and a summary of these values, where-

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from this summary, the points for the curve in FIG. 4 for a mean of 192 μg NTG / cm (corresponding to 16.8 mg of ointment, ie 16.8 100 0.02 won-

1.75

have been. The times in the table relate to the time that has elapsed up to that point and are given in hours and tenths of an hour. The individual values for (Cum. % NTG) are calculated as above.

909849/0942

Table I.

Applied (cum. % NTG) after the specified time

Samples amount of ointment

No. (mg) 1h 2h 3h 4h 6h 7.8h 21.9h

1 14.74 9.20 27.72 44.16 57.05 73.17 82.62 95.80

2 13.83 9.86 28.57 45.27 58.49 73.88 83.00 92.57

3 21.78 2.35 7.67 14.14 20.98 32.61 41.44 63.70

ο average 16.8 7.1 21.3 34.5 45.5 59.0 69.0 84.0

co from 1-3 * + + + + + + "+ +

"4.4 4.2 11.8 17.7 21.3 23.6 23.9 17.0

CD. ·

* "" * - standard deviation

'co

IV) NJ

The cumulative amount of NTG that is per cm of skin in each Time interval has passed, as in Fig. 4. is given, calculated from the summary of the values according to table I (e.g. for 192 / Ug applied NTG / cm).

Repeated tests 4 through 6 (which contained approximately eight times the amount of NTG as samples 1 through 3) were carried out in the same way. Table II gives the values obtained.

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g09849 / 0942

Table II

CD O CD

Amount of ointment applied (cum. % NTG) after the specified time

No. (mg) 3.9h '7.6h 11.9h 16h 19.9h 23.9h

. 4th 1 38.6 VJl 1 41.45 6th 1 23.2 middle
from 4-6 * 1 34.4

8.8 18.4 28.3 37.3 44.7 51.0 3.2 8.4 15.1 21.6 28.2 34.4 10.8 21.0 32.0 40.7 48.5 55.6

7.5 15.9 25.1 32.2 40.5 47.0

3.9 6.7 8.9 10.2 10.8 11.2

CB I

* + Standard deviation ^

2322792 3 «

The values plotted in FIG. 4 indicate that the 8-fold increase in the NTG content (using the 8 times the amount of the same preparation) to an extension of the time in which the drug with essentially linear velocity (zero order) is absorbed by about 4 hours (which is after Prior art was customary) leads to about 24 hours without any appreciable effect on the rate of release occurs during the period of linear absorption. So is the flow rate (/ Ug NTG / ciÄh) for samples 1 to 3 during the period of linear absorption 24.7, while for samples 4 to 6 is 30.4. The flow rate the slope of the best straight line that can be drawn through the points in the drawing is determined by linear regression analysis. The professional world has long tried to achieve such results.

The data and results of Examples 2 to 4 were obtained and treated in the same manner as in FIG Example 1 given, although variations in the composition of the preparation were made from batch to batch became.

Example 2

Effect of different amounts of lanolin in the accessory

fl Ώ C!

Preparation for / ÄDsorption profile of NTG over 24 hours.

Figure 5 is a graph of the normalized means and regression points relative to three Repetitions, each showing the effect of the lanolin content in the preparation according to the invention. In Table III the samples on which the tests were carried out are explained.

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Table III Flow velocity

Preparation q /
/ Q
lanolin angry
NTG amount (with
tel / Ug / cm) / Ug NTG (+ Standard error) Correlation
coefficient tion 0 1725 cm ^ h (+ 1.8) 0.981 D. 5 1666 40.7 (+ 1.3) 0.994 E. 10 1787 ' 48.6 (+ ^ O) 0.956 F. 20th 1673 56.6 (± 5.8) 0.973 G 87.7

All of these preparations (D to G) contained 2 % NTG (added to lactose powder containing 10% NTG as explained above) and the specified amount of lanolin. The remainder of the 100% formulation was white petrolatum, USP. They were made by triturating 10% NTG lactose powder in lanolin and then adding all of the petrolatum with a spatula on a glass plate. All samples were covered with a saran film during the test.

From Fig. 5 it can be seen that the presence of lanolin in the preparations increases the rate of absorption of the NTG, the effect increasing with increasing amounts of lanolin. The rate of absorption remains during the experiment with a given preparation, however, it remains constant, regardless of the amount of lanolin present, until the supply

the NTG is essentially depleted so that / linear absorption can no longer be maintained. The batch, which contains 20 % lanolin, is absorbed very quickly, but the linear absorption is only maintained for 8 hours.

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It appears that the variation in the rate of absorption. Surface effects (on the surface of the skin), caused by the lanolin, which gives you a convenient way to control the flow rate to steer accordingly. This, together with a variation in the area of skin to be treated, allows control the rate of delivery and · the drug to the patient.

Example 3

Effect of different amounts of wax in the preparations according to the invention on the absorption profile of NTG over 24 hours.

Figure 6 is a graph of the normalized means and regression points over three replicates each approach, the effect of the wax (paraffin) content shows in the preparations. Table IV lists the samples on which these tests were carried out. All samples were covered with saran. .

Table IV

Flow rate applied

Preparation %
' Wax NTG amount (Wed
ρ
tel / Ug / cm) t- / ug NTG (+ Standard error) - Correlation
coefficient tion O 1555 cm (+ 3.4) 0.962 H 10 1623 48.5 (+ 3.3) 0.948 I. 20th 1667 39.0 (± 2.6) 0.973 J 30th 1614 42.9 (+ 1.8) 0.985 K 90984 41.1 31: - 9/0942

These preparations contained 2 % NTG (incorporated in lactose powder containing 10% NTG) in a petrolatum vehicle with 10 % lanolin and various amounts of wax as indicated. The preparations were made in the manner indicated above and the samples were covered with a saran film during the experiment. It was found that the higher the proportion of wax, the higher the softening point of the preparation and the stronger its consistency. At the same time, the rate of leaching decreased as the proportion of wax increased.

The properties of the preparation (both absorption and consistency) can be varied by adding Amounts of lanolin and wax can be controlled individually or in combination.

Example 4

Effect of different ISBkel on the absorption profile from NTG over 24 hours.

The graph in Fig. 7 was obtained in the same manner as in the previous figures, except that four replicates were made for the experiments with the non-fatty ointment. In Tab. '.V the composition of the various samples is given.

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Table V

Flow rate applied s

Preparation NTG (medium ^ u * NTG _(st d.Fehler)

tung Description / ^u S / ^cm ) _cm ^ _xn Coeff.

C non-fat 1401 46.75 (+5.45) 0.917 ointment

B lanolin- 1536 30.43 (+4.12) 0.888 Petrolatum

The preparation of the preparations is indicated above (both contain 2 % NTG). The samples were covered with saran foil during the experiment.

The NTG was absorbed from the non-fatty ointment preparation at a much greater rate than from the lanolin-petrolatum preparation, probably again due to the difference in the surface conditions (on the ^ SaA? preparation) caused by the medium. In fact, the rate of absorption is so high that the NTG supply is so exhausted after about 16 hours that linear absorption no longer takes place.

Example 5

Associations according to the invention

On the middle part of the adhesive side of an 8x10 cm A large piece of microporous medical tape became a 5 x 8 cm piece of 101.6 / Ug thick polyethylene film upset. This gave a plaster with an adhesive edge (the one on the long side 1 cm and on the broad side

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1.5 cm "wide (ταπί the polyethylene film). Approximately 3 g of a lanolin-paraffin-petrolatum ointment containing 2 % NTG, preparation A) was applied as a substantially even layer. The surface was heated to create a smooth surface An 8 × 10 cm piece of wax paper was applied so that it covered the adhesive edge and the ointment area. The resulting plaster (containing on average about 1500 / Ug NTG / cm in the ointment area) is able to topically deliver NTG at a rate substantially zero order (constant) over an extended period of time (up to 24 hours or more).

Similar bandages or plasters that have been obtained with a 101.6 μm thick film made of polyester, aluminum or a layer of polyurethane foam instead of the polyethylene film possessed essentially the same characteristics with respect to topical administration of NTG.

A plaster or bandage comprising a crosslinked polyurethane foam, which is laminated with a polyethylene film was also used and is preferred according to the invention .

Example 6

Production of a nitroglycerin polymer powder

To a mixture of 6.46 g of polyethylene powder and 15 ml Acetone, 6.5 ml of a 10% strength (by weight) acetone solution of nitroglycerin (a total of 0.5 g of nitroglycerin) were pipetted. The mixture was held at approximately 24 ° C while the acetone was evaporated to give the desired powder, with the nitroglycerin absorbed on polyethylene.

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here

Samples of this carrier were tested for impact sensitivity using standard impact tests: a 2000 g brass solder was dropped onto the sample from a height of about 122 cm, which corresponds to a moment of 1189.3 kg / cm (555 ft lb / in. After 5 tests no explosion had occurred, it was closed, the material is stable, the powder obtained was analyzed and found to contain 7.18% nitroglycerin.

Example 7

Manufacture of a pharmaceutical preparation

A mixture of 7.5 grams of a styrene-isoprene-styrene block copolymer ("Kraton" 1107 from Shell Oil Company) 142.8 grams of unscreened polyethylene powder and 1215 grams of light mineral oil (NF) was added by heating the components to 140 ° C Stir processed into a solution. The solution was poured in small amounts in a container that was cooled in an ice-acetone bath to -15 ° C, was being avoided that the temperature above about 0 ⁰ C increased (ie, by very fast cooling) and was able to freeze. 250 g of propylene glycol (USP), 564.3 g of a carrier containing 8.86 % nitroglycerin on polyethylene powder (prepared according to Example 6) and 195.4 g of sieved polyethylene powder were added successively to this ointment at about 23 ° C. The mixture was mixed thoroughly until the ointment appeared homogeneous. It was then passed through a grinder 3 times. A further 125 g of polyethylene powder were then added with stirring in order to bring the total nitroglycerol content to 2%.

909849/0942

Claims (16)

Claims 1. means for topical administration of nitroglycerin, characterized in that it is for continuous administration in the form of a bandage or plaster exists, consisting of a) a base that forms a surface of the dressing and b) a drug supply containing nitroglycerin together with a carrier that allows the passage of the nitreglycerin is permeable and wherein the drug supply is kept in direct contact with the skin and over provides a constant rate of absorption of nitroglycerin through the skin for at least about 8 hours. 2. Means according to claim 1, characterized in e t that the drug supply is surrounded by a non-irritating self-adhesive edge, with the help of which the drug supply is kept in direct contact with the skin. 3. Means according to claim 2, characterized in that the adhesive is rubber-like, usually acrylate or urethane type tacky agent with a -Z- 909849/0 202279? 100% modulus less than 7 kg / cm. 4. Means according to claim 1 "to 3 _}, characterized in that the surface of the drug supply is covered by a protective layer which can be removed before the bandage is applied. 5. Means according to claim 1 to 4, characterized in that that the drug supply contains the nitroglycerin in a lanolin petrolatum preparation. 6. Means according to claim 1 to 4, characterized in that that the nitroglycerin is contained in a non-fatty ointment preparation. 7. Stable pharmaceutically acceptable carrier for nitroglycerin, characterized in that it consists of a polymeric powder suitable for the production of an ointment and nitroglycerin in an amount of about 1 to 20 parts of nitroglycerin per 100 parts of the total vehicle is absorbed. 8. A carrier according to claim 7, characterized in that 3r approximately 1 to 10 parts of nitroglycerin to 100 parts of the total carrier. 9. Carrier according to claim 7 or 8, characterized in that that the polymer powder suitable for the production of an ointment is selected from the group: polyethylene, Polypropylene, polybutylene, polymethylbutylene. 10. Carrier according to claim 7 to 9, characterized in that the polymer for the production of a Ointment suitable powder is polyethylene. - 3 BO 9849/0942 ^ 32279? 11. A method for producing the carrier according to claim 7 Ms 10, characterized in that a solution containing 1 to 20 parts of nitroglycerin in one suitable volatile solvent with a slurry of 99 to 80 parts of a polymer, for the preparation an ointment suitable powder mixed in the same or a compatible volatile solvent, the Sum of the parts of nitroglycerin and powder is 100, and then the solvent (or solvents) evaporate. 12. The method according to claim 11, characterized in that that acetone is used as the solvent for the solution and the slurry, respectively. 13. nitroglycerine-based formulation which is suitable for topical administration, characterized in that it comprises about 40 to 90 wt .-% of a fat viscous base substance and about 10 to 60 wt, -% of a solid, non-irritating, suitable for producing a string powder contains, wherein the viscous base substance is selected from the group: solid petrolatum, animal oils, mineral oils and synthetic oils, the oils have been thickened by an agent from the group of waxes and hydrocarbon polymers and wherein the powder suitable for the production of an ointment is a polyolefin with 2 to 6 carbon atoms in the repeating unit, a molecular weight of about 3000 to 150,000 and an average maximum particle size of less than about 30 μm, the viscous basic substance at a temperature below 50 ⁰ C essentially of that for the preparation of the Ointment suitable powder is not absorbed and the fatty viscous basic substance m is mixed ith the Pulvertei a temperature of less than about 50 ⁰ C, and on the ver Puit nitroglycerine in an amount of 0.5 to 4 Gev "- is absorbed%, based on the total preparation. - 4 90984 9/0942 2322792 14. Preparation according to claim 13, characterized in that that the powder suitable for making the ointment is polyethylene. 15. Preparation according to claim 13 or 14, characterized in that the thickener about 0.3 to 0.5 wt .-%, based on the viscous base substance of an amorphous elastomeric, unvulcanized block copolymer are added, consisting of terminal styrene blocks with a glass transition temperature above about 25 ⁰ C and a molecular weight between about 2000 and 100,000 and an average isoprene block having a glass transition temperature below that of the engständigen blocks. 16. Process for the preparation of nitroglycerin-containing Preparation according to Claims 13 to 15, characterized in that one a) a solution containing 1 to 20 parts of nitroglycerin in a suitable volatile solvent with a slurry from 99 to 80 parts of a polymeric powder suitable for making an ointment in the same or a compatible liquid solvent mixed with the sum of the parts of nitroglycerin and the powder 100 and then the solvent or solvents evaporate, the nitroglycerin as an adsorbate on the polymeric particles is retained and b) mixing the resulting nitroglycerin-containing support with a composition comprising about 40 to 90 wt -.% of a fat viscous base substance and about 10 to 60 wt .-% of a solid, non-irritating, suitable for preparation of an ointment powder, wherein said viscous base substance is selected from the group: petrolatum, animal oils, mineral oils and synthetic oils and the oils have been thickened with an agent from the group of waxes and hydrocarbon polymers and where the for - 5 - 909849/0942 Powder suitable for preparing the ointment comprises a polyolefin having 2 to 6 carbon atoms in the repeating unit, a molecular weight of about 3000 to 150,000 and a mean maximum particle size of less than about 30 µm, and the viscous matrix at a temperature below about 50 ⁰ C is not absorbed by the appropriate for the preparation of the ointment powder substantially and the rich viscous matrix with the ointment forming powder at a temperature of less than about 50 ⁰ C is mixed and the nitroglycerin-containing carrier is added in an amount such that the proportion of Nitroglycerin in the entire preparation is approximately 0.5 to 4 Gevf .-% « 6224 909849/0942