HK1018199A - Transdermally administrable medicament with ace inhibitors - Google Patents

Description

Transdermal delivery system containing ACE inhibitor

Angiotensin converting enzyme inhibitors (ACE inhibitors) are now being used more and more extensively for the long-term treatment of hypertension. ACE inhibitors are not only well tolerated, but their activity is also very stable. The first drug of the ACE inhibitor class is captopril, a very hydrophilic substance that is active in its unmodified form. The oral bioavailability of captopril is about 70%. Newer ACE inhibitors, such as enalapril, are metabolized from their precursor form to the active component enalaprilate, the acidic form, upon passage through the liver. Like enalapril, the ACE inhibitors ramipril, cilapapril, trandolapril, benazepril or fosinopril are lipophilic parent drugs for the active drug in the form of actually dicarboxylic acids. In this case, the carboxyl groups of the respective ACE inhibitors are esterified, as a result of which these substances become more lipophilic and moreover more favourable for oral absorption. However, the oral bioavailability of these parent drugs is always lower than captopril. For example, benazepril is about 28% and trandolapril is about 40-60%. It is known that these substances with low bioavailability depend on the metabolic capacity of the patient. This means that the resulting plasma concentrations vary greatly. However, the drastic changes in blood concentrations of ACE inhibitors or their active forms lead to uncertainty in the time of action. In order for ACE inhibitors to function independently of the metabolic profile of the patient, it is desirable to have a pharmaceutical dosage form that allows stable, reproducible, systemic administration of the active compound. Transdermal administration of the active compound allows the drug to bypass the first pass metabolism of the liver, thus eliminating the change in liver metabolism. If the parent drug or its active form of an ACE inhibitor can now be made systemically transdermal, reliable stabilization can be achieved.

WO-a1-9323019 has disclosed a transdermal drug delivery system comprising an ACE inhibitor, the system further comprising (a) a non-permeable cover layer (base foil); (b) a layered body having a hollow space; (c) a device for controlling the release of an active compound (claim 1); and (e) a tear-off paper-based cover layer (release liner) (page 12, lines 7-8).

Transdermal systems comprising ACE inhibitors are further described in EP-A2-0439430 (depot TTS) and EP-A2-0468875 (matrix TTS). According to EP-A2-0468875, silicone elastomers are used as matrix materials.

It is an object of the present invention to provide a transdermal delivery system for ACE inhibitors, in particular ramipril, tandolapril and/or their therapeutically active salts, which is considerably improved compared to the prior art.

In particular, it is an object of the present invention to provide a transdermal delivery system for ACE inhibitors in which activity can be achieved for up to about one week, which will enable continuous release of the active compound and a therapeutically effective plasma concentration for a period of about one week, e.g. over 0.5 ngtrandolapril/ml.

To this end, the present invention provides a transdermal system having a polyisobutylene or butyl rubber based matrix and comprising at least one ACE inhibitor. According to the present invention it has surprisingly been found that lipophilic ACE inhibitors or their active forms, which are otherwise difficult to penetrate human skin, can easily penetrate the skin and give continuous, stable blood concentrations by means of transdermal delivery systems with a polyisobutylene base or a butyl rubber base.

According to the invention, the release rate of the active compound from, for example, a polymer matrix can be up to 0.01 to 0.1mg of active compound/cm per 24 hours²In particular 0.025 to 0.050mg of active compound/cm²Thus, the transdermal systems according to the invention allow the plasma concentration of the active compound to be maintained at a therapeutically active amount. For trandolapril, for example, therapeutically active concentrations in blood greater than about 0.5ng/ml can be achieved.

Suitable polyisobutylene or butyl rubber substrates are well known to those skilled in the art, for example, see Higgins et al in Satas, Handbook of pressure Sensitive Adhesive Technology, 14: 374, and the like, butyl rubber and polyisobutylene; van Nostrand Reinhold, New York (New York).

In the transdermal system according to the invention, the concentration of the ACE inhibitor is at least 5% by weight, in particular 10 to 20% by weight, based on the weight of the matrix.

The ACE inhibitors used may be either the parent drug or the active form.

Examples of ACE inhibitors which may be mentioned are ramipril, trandolapril and/or their active forms (in acid form), and their therapeutically active salts.

The transdermal system according to the present invention may comprise a penetration enhancer, such as 2-octyldodecanol (Eutanol G).

The transdermal systems according to the invention can use different forms of, for example, membrane-or matrix-control systems.

Thus, the transdermal system according to the present invention may be a patch having a drug storage device (drug storage type patch).

According to a particular embodiment, the patch of the type with a drug reservoir is characterized in that: (a) a non-permeable cover layer (base foil); (b) a layered body having a hollow space; (c) a microporous or semi-permeable membrane; (d) a self-adhesive layer (adhesive layer), and (e) if appropriate, a tear-off cover layer (release liner).

In this case, the layered body having the hollow space may be formed with the covering layer and the film.

The microporous or semipermeable membrane may be composed of an inert polymer, such as polypropylene, polyvinyl acetate, or silicone.

According to other embodiments of the present invention, the drug reservoir type patch is characterized in that: (a) a non-permeable cover layer (base foil); (b) an open cell foam, a closed cell foam, a fabric-like layer or a mesh layer as a drug storage device; (c) a self-adhesive layer (adhesive layer) if the (b) layer is not self-adhesive; and (d) if appropriate, a tear-off cover layer (release liner).

The drug reservoir may be formed, for example, by a hollow space or other means. In this case, the storage device is filled with the active compound/adjuvant mixture. For the accommodation of the active compound in the drug storage device reference is made to the prior art concerning drug storage devices. After the cover film (protective film) is torn off and the patch is applied to the skin, the active compound penetrates (permeates the film, if any) through the cover layer together with the adjuvants and penetrates into the skin.

If a membrane is provided, the release of the active compound can be controlled according to the pore width effect or has no effect on the release of the active compound from the system.

If the drug reservoir is an open-cell foam, a closed-cell foam, a textile-like layer or a mesh layer, the active compound/adjuvant mixture is in adsorbed or finely divided form. In this case, a microporous or semipermeable membrane may not be used, and the layer forming the drug reservoir may be self-adhesive or, if not, carry a self-adhesive layer (adhesive layer).

According to a particular embodiment, the transdermal system according to the invention is characterized in that: (a) a non-permeable cover layer (base foil); (b) a matrix layer for the active compound; (c) active compound permeable contact adhesive layer (if layer (b) is not self-adhesive); and (d) if appropriate, a tear-off cover layer (release liner).

The substrate used in the present invention may be a self-adhesive polyisobutylene adhesive.

The present invention will be described in more detail below by way of examples.Practice ofExamples 1 to 5

Transdermal Therapeutic System (TTS) providing a matrix type, characterized in that it is composed of: matrix: polyisobutylene Adhesive (MA24, available from Adhesive)

Research inc., Glen Rock, Pennsylvania, USA) cover film: polyester film (Hostaphan RN 19) protective film: polyester film (Gelroflex PET 75 μm 1-S) or

Coated paper film (Gelrolease 603/100)

DRS) matrix component: trandolapril 10% by weight

Eutanol G5% by weight

Polyisobutylene binder (dry weight) 85% by weightComparative example 1

In place of the polyisobutylene adhesive, a silicone adhesive (BIO PSA X74302) was used here.

The results obtained are shown in the following table.

Comparison of example 1 with comparative example 1 shows that the release of the active compound in the system according to the invention remains stable over a period of 20 days, whereas in comparative example 1 the decrease is very rapid.Use ofExample 1

In an in vivo comparative study of the TTS of the present invention, pharmacokinetic properties of TTS administration were tested on 6 healthy subjects using an oral dose of trandolapril (capsule). The study was designed as open, 2-phase, interleaved, TTS administration over a 7-day period (4 days for 1 TTS followed by 3 days for 1 TTS), whereas in the comparative experiment, trandolapril capsules containing 2mg of compound per capsule were administered daily for a total of 7 days. Blood samples were taken at the following times after dosing: -0.5; 0; 2; 4; 6; 8; 10; 12; 24; 48; 72; 96; 98, respectively; 100, respectively; 102, and (b); 104; 106; 108; 120 of a solvent; 132; 144, 144; 156; for 168 hours.

Pharmacokinetic results show that TTS has a substantially different plasma concentration profile compared to capsules. In contrast to capsules, it is also desirable for therapy that the blood level remains stable for 3 or 4 days per administration. After oral administration, the blood drug level rises rapidly, in fact reaching 5ng/ml within 2 hours. The elimination half-life is about 24 hours. In contrast, the duration of the plasma concentration after TTS administration is more uniform. In the first 4 days of use, a slight uniform increase in plasma concentration was observed, from 0.3ng/ml after 6 hours to 1ng/ml after 96 hours. The TTS was changed after 96 hours, after which the blood concentration did not rise significantly during the second dosing period (fig. 1). Thus, the plasma concentration profile after TTS administrationVery close to the ideal stable blood concentration during treatment. Undesirable peaks in blood concentration, which are often associated with undesirable side effects such as sudden blood pressure drops, are safely avoided.

Examples	Adhesive agent	Active compound (b): trandolapril (%)	Penetration enhancer [% ]]	Release of active Compound (mg/cm)2)			Crystallization of
								Days of preparation	Skin penetration (24h)	Diss(6h)
				E1	Polyisobutenes	3					0	4720	0.013	0.0080.008	Is free of
E2		5	0				4720	0.014	0.0090.011	Is free of

E3		10	0	472037	0.0270.023	0.0190.019	Is free of
								E4		10	10CitiolV	13	0.044		Is free of
E5		10	5EutanolG	8	0.061		Is free of
								CE1	Siloxanes	3	0	0152633	0.0650.0300.017	0.076	Is free of

Claims (15)

1. Transdermal system having a matrix based on polyisobutylene or butyl rubber and comprising at least one angiotensin converting enzyme inhibitor (ACE inhibitor).

2. Transdermal system according to claim 1, characterized in that the concentration of the ACE inhibitor is at least 5 wt. -%, in particular 10 to 20 wt. -%, based on the weight of the matrix.

3. Transdermal system according to claim 1 or 2, characterized in that the ACE inhibitor is present as the parent drug or in its active form.

4. Transdermal system according to any one of the preceding claims, characterized in that the ACE inhibitor is ramipril, trandolapril and/or their active forms (acid forms) and/or their therapeutically active salts.

5. Transdermal system according to any one of the preceding claims, characterized in that the transdermal system comprises a penetration enhancer, in particular Eutanol G.

6. The transdermal system according to any of the preceding claims, characterized in that the transdermal system is a patch with a drug reservoir (drug reservoir type patch).

7. The transdermal system according to claim 6, characterized in that (a) a non-permeable cover layer (base foil); (b) a layered body having a hollow space; (c) a microporous or semi-permeable membrane; (d) a self-adhesive layer (adhesive layer), and (e) if appropriate, a tear-off cover layer (release liner).

8. The transdermal system according to claim 7, characterized in that the lamina with hollow spaces is formed by a cover layer and a membrane.

9. The transdermal system according to claim 7 or 8, characterized in that the membrane consists of an inert polymer, in particular polypropylene, polyvinyl acetate or silicone.

10. The transdermal system according to claim 6, characterized in that (a) a non-permeable cover layer (base foil); (b) an open cell foam, a closed cell foam, a fabric-like layer or a mesh layer as a drug storage device; (c) a self-adhesive layer (adhesive layer) if the (b) layer is not self-adhesive; and (d) if appropriate, a tear-off cover layer (release liner).

11. The transdermal system according to one of claims 1 to 5, characterized in that (a) a non-permeable cover layer (base foil); (b) a matrix layer for the active compound; (c) active compound permeable contact adhesive layer (if layer (b) is not self-adhesive); and (d) if appropriate, a tear-off cover layer (release liner).

12. The transdermal system according to claim 11, characterized in that the matrix is a self-adhesive polyisobutylene rubber adhesive.

13. Transdermal system according to one of claims 7 to 12, characterized in that the cover layer (base foil) is formed from polyester, polypropylene, polyethylene or polyurethane.

14. The transdermal system according to one of claims 7 to 13, characterized in that the tear-off cover layer (release liner) is formed from polyester, polypropylene or paper coated, in particular silicone and/or polyethylene.

15. Transdermal system according to claim 13 or 14, characterized in that the thickness of the cover layer (base foil) and/or the peelable cover layer (release liner) is 5 to 100 μm.