|Title of Invention||
"A PHARMACEUTICAL COMPOSITION FOR TRANSDERMAL/TRANSMUCOSAL DELIVERY"
|Abstract||This invention relates to a pharmaceutical composition for transdermal/transmucosal delivery of at least one drug comprising in combination 5-20% by wt % drug; 5-10% by wt % permeation promoter; 20-80% carrier; 5-10% of a plasticizer such as dibutyl phthalate.|
|Full Text||FIELD OF INVENTION
This invention relates to a novel skin permeation promoter viz. piperidine hydrochloride for transdermal drug delivery of active ingredients. The compound of the present invention is capable of enhancing skin permeation of drugs and can be used in formulations meant to be delivered through skin or mucous membrane more particularly transdermal drug delivery systems and related devices.
The transdermal route of drug delivery of drugs provides many advantages, and transdermal systems for a wide variety of medicaments are described in U.S. Patents 3,598,122;3,598;123;3,731,683;3,797,494,4,286,592;4,314,557;4,379,454;4,435,180;4,55 ,9,222;4,568,343;4,573,999;4,588,580;4,645,502;4,704,282;4,816,258;4,849,226;4,908,2 7;4,943,435;5,004.610,5,006,342;5,314,694;5,411,740,5,629,019;5,641,504;5,689,097.
One major drawback of transdermal drug delivery of drugs in the presence of stratum corneum as the barrier for skin permeation of drugs. In an effort to overcome this barrier and to increase the skin permeability of drugs in order to deliver drugs in therapeutically effective amounts, it is beneficial to pre-treat the skin with various chemicals or to concomitantly deliver the drug along with a permeation promoter. A number of substances have been proposed for the purpose, as mentioned in U.S. Patents 3,472,931:3,527,864;3,896,238;3,903,256;3,952,099;4,046,886;4,130,643;4130,667;4,29 9,826;4,335,115;4,343,798;4,379,454;4,405,616;4,568,343;4,4,746,515;4,764,379;4,788, 062;4,820,720;4,863,738;4,863,970;4,865,848;4,900,555;4,940,586;4,973,468;5,053,227 ;5,059,426;5,378,730 and 6,267,984. A recent review on "penetration enhances' has been published by Williams and Barry in Advanced Drug Delivery Reviews, Vol.56 (2004) 603-618.
To be pharmaceutically useful a permeation promoter should possess the ability to enhance the skin permeability for at least one and preferably a significant number of drugs. More importantly, it should be able to promote skin permeability so that the drug delivery rate from a reasonably sized system (5-60 cm2) is up to therapeutically effective levels. Moreover, the permeation enhancer when applied to skin, should be non-toxic, non-irritating on prolonged exposure and non-sensitizing on repeated exposure.
It should be compatible with both excipients and drugs, and should work ideally rapidly and the activity and duration of effect should be both predictable and reproducible.
OBJECTS OF THE INVENTION
An object of the present invention is to propose a skin permeation promoter for improved
transdermal delivery of active ingredients.
DESCRIPTION OF INVENTION
According to this invention there is provided a composition for transdermal/transmucosal delivery of at least one drug comprising in combination:-
a) at least one drug,
b) a permeation enhancing amount of permeation promoter comprising 5-
10% by weight of piperidine hydrochloride,
The invention provides compositions and devices for transdermal administration of a least one drug to the systemic circulation of a patient, at a therapeutically effective rate, by permeation through a body surface or membrane comprising at least one active ingredient and permeation enhancing amount of a penetration promoter comprising piperidine hydrochloride. The invention further provides a method for the transdermal coadministration of a drug at a therapeutically effective rate together with a skin permeation enhancing amount of the piperidine hydrochloride penetration promoter.
A farther aspect is to increase the transport of drugs across the skin following application of a transdermal therapeutic system and attainment of the desired therapeutic flux level.
According to the invention, piperidine hydrochloride and the drug to be delivered are combined with a carrier, and both in relationship to the appropriate body surface, and maintained in place for the desired period of time. The drug and said penetration promoter are typically mixed within a physiologically compatible carrier for matrix which may be applied directly to the body surface or skin as an ointment, solution gel, cream, suppository or sublingual or buccal tablet, for example, although not required, to occlude the site of administration. Such compositions may also contain other penetration promoters, stabilizers dyes diluents, binders, lubricants, pigments, vehicles, gelling agents and other excipients as are known to the art.
The piperidine hydrochloride enhancer of this invention has a permeation enhacing effect on the transport of drugs through body surface tissues generally is addition to the skin, however because skin is one of the most effective barriers to the permeation of drugs into the body. The effect of piperidine hydrochloride on skin permeation makes its exactly useful is transdermal delivery. The following description of embodiments of the invention is therefore directed primarily to improving systemic delivery of these drugs by permeation through the skin.
The above enhancer containing formulation according to this invention comprises a carrier with a drug and said penetration promoter with or without adhesive lamination on the backing and release liner. In addition to the drug and penetration promoter the carrier may also contain dyes, pigments, gelling agents, vehicles, anti-irritants, inert fillers and other excipients and conventional components of pharmaceutical products or transdermal devices as known to the art. For example the carrier may also be provided with lipophilic polymers for example polyacrylates, and/or hydrophilic polymers for example polyvinylpyrrolidone and/or an anti-irritant such as a corticosteroid for example hydrocoiiisone.
In the present invention, the drug is delivered through the skin or other body surface at a therapeutically effective rate (that is, a rate that provides an effective therapeutic result) and the piperidine hydrochloride permeation promoter is delivered at a permeation enhancing rate (that is a rate that provides increased permeability of the application site of the drug) for a predetermined time period.
A preferred embodiment of the present invention is a monolithic matrix comprising of 5-20% of durg, 5-10% and more preferably 10% piperidine hydrochloride, 5-10% of a plasticizer for example dibutyl phthalate and 20-80% of a carrier such as film forming polymer(s) for example eudragit and polyvinylpyrrolidone.
In accordance with the carrier comprises an inert polymeric material which controls the release behaviour of the drug and promoter. The promoter modifies the permeability of the skin.
The devices of this invention can he designed to effectively deliver a drug lor a prolonged time period of up to 7 days or longer. Seven days is usually the maximum time limit for application of a single device because the skin is a adversely affected by a period of occlusion in excess of 7 days. Wherever it is desired to provide drug delivery for more than 7 days (for example when a hormone is used for a contraceptive effect), it is suggested when one device has been in place on the skin for its recommenced lime period, its is replaced with a fresh device, preferably on a different site of skin.
The method and procedures by which the present invention can be practiced can be described by the following non-limiting examples:
The effect of various penetration enhancers on transdermal permeation oi pinaeidil monohvdrate (PM) was studied. The drug permeation experiments were conducted using a hori/ontal glass diffusion cell on albino rate skin.
The hori/ontal glass diffusion cell consisted of two half cells-donor and receiver. Previously excised abdominal skin of an albino rat was washed with distilled water and mounted between two half cells such that the stratum corneum faced the drug donor compartment whereas dermis faced the receiver side. The receiver ceil was filled with 10 ml of isoionic phosphate buffer (II'B) of pi I 7.4 and isopropyl alcohol (IFA) (7:3 v/v) which was agitated with a teflon magnetic rotor. The temperature of the receiver phase was maintained at 32-37°C. The donor compartment was filled with 10 ml of pinacidil monohvdrate solution in different vehicles with and without penetration enhaneer(s). The receiver fluid was withdrawn and replaced with the same volume of fresh fluid. The samples were littered and analyzed for drug content at 257 nm spectrphotometricallv. The drug (lux v.as determined from the slope of the plot between cumulative amount of drug permeated (mg/cirr) v/s time (hours). The permeability coefficient (Kp) was deduced by dividing the flux by drug concentration in donor cell. The enhancement factor (El:) was calculated by dividing the Kp with enhancer by Kp without enhancer (control).
The in'lluence ol' various enhancers namely, dimetln Isulfoxidc (DMSO). dinetliylformamide (DM1-). propylene glyeol (I'Ci). oleic acid (OA). tween 20 (T-20) and turpentine oil (TO) on the skin permeability ofpinacidil monohydrate was investigated and the results are shoun in Table
TABLE 1 : Influence of Vehicle and Penetration Enhancers on Skin Permeability of Pinacidil Mouohvclratc
The monolithic matrix type transermal drug delivery systems of meloprolol larlrale (Ml) sere prepared by film casting technique on mercurv substance and characterized in vitro by drug release studies, skin permeation studies and drug excipients interaction analysis.
I-'or fabrication of patches. polymeric solution was preferred by dissolving Eudragil RL100 and PVP K-30 (ratios 2:
The above TDDS was evaluated for in vitro drug release using LISP apparatus 5 (paddle over disc assembly) and ex vivo skin permeation using a glass diffusion cell and rat skin, the drug-excipients interaction studies \\erc carried out by comparing the indicated TDDS formulations \\ilh the pure drug and placebo formulations on the basis of assay. I V. IR and II.C' analysis. The stability studies uere conducted according to 1C II guidelines b\ storing the TDDS al 4().().5"C' and 75±5% Rll lor 6 months. The samples were withdrawn al 0. 30. 60. 90 and 1X0 drugs and were analy/er for drug content by I H'l.C.
Cumulative amount of drug released in 48 hours from the four formulations were 61.5%. 75.4%. 84.3% and 94.5%. respectively. The corresponding values for cumulative amount of the permeated drug for the said formulations were 53.5%. 62.5%. 69.8% and 78.2%. respecli\cl\. On the basis of in vitro drug release and skin permeation performance, formulation MT-4 \\as found to be better than the other three formulations and it was selected as the optimized formulation. No apparent chemical interaction was observed between the drug and UV cxcipients in formulation MT-4 on performing UV. IR. assay and TLC analyses. The optimized formulation (MT-4) was reasonably stable with a tentative shelf life of 2 years;
The invention has been described in detail with particular reference to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the scope and spirit of the invention.
1. A pharmaceutical composition for transdermal/transmucosal
delivery of at least one drug comprising in combination:-
a) 5-20% by wt % drug selected from the class of antihypertensives;
b) 5-10% by wt % permeation promoter piperidine hydrochloride;
c) 20-80% carrier selected from polyacrylates, polyvinylpyrrlolidones, ethycellulose, polyvinyl acetate, cellulose acetate and other suitable film forming polymers;
d) 5-10% of a plasticizer such as dibutyl phthalate.
2. A pharmaceutical composition as claimed in claim 1 wherein the drug is preferably in an amount of 5-10% by wt.
|Indian Patent Application Number||2391/DEL/2004|
|PG Journal Number||07/2012|
|Date of Filing||30-Nov-2004|
|Name of Patentee||JAMIA HAMDARD (HAMDARD UNIVERSITY)|
|Applicant Address||HAMDARD NAGAR, NEW DELHI-110 062, INDIA.|
|PCT International Classification Number||CO7D 223/08|
|PCT International Application Number||N/A|
|PCT International Filing date|