INTRODUCTION:

A transdermal patch is a mediated adhesive patch placed on the skin to deliver a time released dose of medication through the skin for treating topical or systemic illness. Since early 1990, this dosage form of transdermal therapeutic system has been available in the pharmaceutical market. Such a system offers a variety of significant clinical benefits over others, such as tablets and injection.^(1,2,3)

Transdermal drug delivery system can deliver certain medication to systemic circulation in a more convenient and effective way than is possible with conventional dosage form. The potential of skin as a path of drug administration has been amply demonstrated by the acceptability of marketed therapeutic systems^(4).Administration of systemic drugs using a transdermal patch represents a non invasive route, with improved patient compliance. This route of administration prevents passage through the gastrointestinal tract and maintains constant plasma levels for prolonged period of time ⁽⁵⁾.

Also for the transdermal route of administration, peak plasma levels of drugs are reduced leading to decreased side effects and it avoid presystemic and systemic first pass metabolism and eliminates the need for intravenous access^(6,7,8)

Transdermal route is a potential mode of delivery of lipophilic drugs in the systemic circulation.⁽⁹⁾ It controls of the area of application, amount applied, release kinetics and prolongation of application time ⁽¹⁰⁾.

Methyl cellulose are widely used in many pharmaceutical formulation.⁽¹¹⁾ This polymer was used along with Dibutyl phthalate as plasticizer for the formulation of patches. PVP was used as copolymer. The primary role of plasticizers is to improve flexibility and processability of polymers by lowering the second order transition temperature ⁽¹²⁾ .Plasticizers are actually low molecular weight serum or liquids which form secondary bonds to polymer chains and spread them apart. Thus, plasticizers reduce polymer- polymer chain secondary bonding and provide more mobility for the macromolecules, resulting in a softer, more easily deformable mass.⁽¹³⁾

Chlorpheniramine, classified as an antihistamine, is a propylamine, derivative (alkylamines) and has a molecular weight of 390.87 (chlorpheniramine maleate, (CPM). Antihistamines such as CPM are H₁ – receptor antagonists and are utilized in the treatment of allergy. They prevent, but do not reverse the responses medicated by histamine. CPM antagonizes most of the pharmacological effects of histamine including urticaria and pruritus. Also CPM like other antihistamines, produces a drying effect on various mucocas by preventing the responses to acetylcholine that are mediated via muscarinic receptors ^(14,15)

The CPM is a typical cationic amphiphilic amine drug (CAD); characterized by the hydrophobic ring structure of the molecule and the hydrophilic side chain with a charged cationic amino group. This above physio chemical property of CPM is similar to other CADs. Therefore it was choosen as a model drug for the present study.⁽¹⁶⁾

OBJECTIVES:

Specific objectives are:

1. To develop CPM matrix patches with methyl cellulose with and without PVP as co polymer, with different percentage of dibutyl phthalate as the plasticizer.

2. To study the possible drug polymer interactions by ATR-FTIR.

3. To measure the patch thickness and swelling index of the patches.

4. To measure drug content, moisture content and moisture uptake of the patches.

5. To study the percentage release and percentage drug permeation from the patches.

6. To develop transdermal therapeutic system on the basis of the above data.

MATERIALS:

Methyl cellulose(Loba chemicals Pvt Ltd, Mumbai), Polyvinyl pyrolidine-PVP(Sigma aldrich, steinheim), Chlorpheniramine maleate(Green waves Pvt Ltd-Juggat pharma, Banglore), Dibutyl phthalate-DBP(SD fine chemicals Ltd, Mumbai), Ethanol(Changshu Yangyuan chemicals, China) and Chloroform were from Qualigens fine chemicals, Mumbai.

METHODS

1. Partition co-efficient of CPM in n-octanol/phosphate buffer system

The partition co-efficient of drug was determined by taking equal amount of n-octanol and phosphate buffer pH 5.8 in a separating funnel^(18,19).

An adequate quantity of CPM was added to this and was shaken for 1 hour. The aqueous solution was separated out and the absorbance was measured at 262 nm.

Partition coefficient of drug

2. Swelling index of polymers

Swelling studies were performed by keeping the polymeric discs in test tubes and measuring thickness as a function of time while swelling. Tubes were kept in vertical position at 37˚C. The dynamic swelling behaviors of the polymeric discs were studied by measuring the thickness of the gel layer as the swelling occurred. Swelling experiment was continued until the equilibrium was reached. The dynamic gel thickness data obtained were translated into a volume-swelling ratio, Q, using the following equation:

Q= V_s/V_d

where V_sis volume of swollen gel and V_d the initial volume of dried gel. Swelling behavior of the polymer is shown in Fig.1.

3. Compatibility study using FT/IR Spectrometer

By using Shimadzu spectrometer the compatibility studies of drug and polymers were carried out. One part of the sample was mixed with three parts of dried potassium bromide and then compressed to give thin transparent pellets. These pellets was scanned under the IR region and the spectrum was obtained⁽²⁸⁾. The spectrum is as depicted in Table: 1 and Fig.2-4.

4. Preparation of patches

Preparation of film was done by solvent casting technique⁽¹⁷⁾.

For the preparation of patches different concentrations of the polymer were weighed and taken followed by addition of 10-20% of PVP as copolymer with uniform slow magnetic stirring then the plasticizer DBP (10-15% of the polymer weight) was added. To this 16 mg of the drug were added to the solution; ethanol:chloroform(1:1) was used as solvent and stirred for 15-20 minutes. Next the total mass was slowly poured in to the centre of SS rings having a backing layer of aluminium foil. The total mass was dried at room temperature for 48 hours. Composition of different formulations are represented in Table: 2.

5. Physical appearance

Transdermal patches prepared were visually inspected for color, clarity, flexibility and smoothness⁽²⁹⁾.

6. Thickness of the patch

The thickness of the CPM Transdermal patches made with methyl cellulose and sodium alginate were measured using digital micrometer⁽²⁸⁾. The thickness of different formulations are given in Table: 3.

7. Drug content of the patch

A known area of the patches was taken and was dissolved in 30 ml of phosphate buffer pH 7.4 in a 50 ml of standard volumetric flask and was shaken for 24 hours. The volume was then made to 50 ml by using phosphate buffer pH 7.4. Amount of drug was determined spectrophotometrically by measuring the absorbance at 262 nm with respect to the standard calibration graph of CPM. The transdermal patches made with above mentioned composition of all excipients excluding drug was used as blank⁽²⁸⁾. The percentage of drug content of various patches are given in Table: 3.

8. Moisture content of the patch

The film was weighed and was then kept in a dessicator containing calcium chloride. The temperature was maintained at 40°C and the patches were dried for 24 hrs. The film was weighed till it showed constant weight. The moisture content was calculated in percentage⁽²⁰⁾ and are mentioned in Table: 3.

9. Moisture uptake of the patch

The prepared patches were weighed and kept in desiccators at room temperature for 24 hrs, which was further exposed to 84% relative humidity by a saturated solution of KCl in a dessicator till a constant weight was achieved. The percentage of moisture uptake was calculated by the formula given below and is tabulated in Table:⁽²¹⁾.

Percentage moisture uptake =

10. Swelling index (SI) of the patch

Swelling index was carried out for the prepared patches. Medicated patches were dried until a constant weight (W₁) in a dessicator over anhydrous calcium chloride for one day at room temperature. These patches were immersed in 100 ml phosphate buffer pH 5.8 at 37°C. Then the excess of water was removed using filter papers and the patches were reweighed (W₂) and was then dried to a get a constant weight (W₃) in a dessicator.

Swelling index was calculated by the following formula^(22,23) and are as reported in Table: 3.

SI =

11. In- vitro dissolution study of the patch^(24,25)

Selected patches were taken and the dissolution was done by using USP type - II dissolution test apparatus by the following method.

A stainless steel disc assembly was taken and the patches were fixed to it. A distance of 25 ± 2mm was maintained between the paddle and the surface of the disc assembly. The vessel was covered to prevent evaporation.

The whole assembly was immersed in 900 ml phosphate buffer pH 7.4 and the temperature was kept at 32°C.100 rpm was set as speed of rotation.

Samples were collected occasionally at 0.25, 0.5, 0.75, 1st, 1.5, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th and 24th hr and replaced with fresh medium. The solution were filtered and then the absorbance was measured at 262 nm . The percentage of drug released verses time was plotted and are as reported in Table: 4 and Fig.5.

12. In vitro permeation study of the patch

The in vitro permeation studies of the prepared patches were done by Franz diffusion cell. This method is been commonly used in most of the published articles^(26,27).

A cellophane membrane is mounted in the diffusion cell having a cross sectional area of 3.14 cm². Membrane was tightly kept between the donor and receptor compartment. Patch was then kept on the upper surface of the membrane. 14.5 ml of phosphate buffer of pH 5.8 was filled in the receptor compartment. The temperature was maintained at 32°C and it was stirred at 60 rpm using a magnet. 1 ml of the sample was taken at time interval of 0.25, 0.5, 0.75, 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th and 24th hr and fresh buffer solution was replaced into it. Samples were then measured at 262 nm by UV spectrophotometer. The observations are tabulated in Table: 6 and Fig.6.

RESULT AND DISCUSION:

1. Partition coefficient of CPM in n-octanol/phosphate buffer system

Partition coefficient of CPM in n-octanol- phosphate buffer pH 5.8 was found to be 0.8518. It indicates that the drug possesses sufficient lipophilicity that meets the requirement of formulating the drug in to a transdermal patch.

2. Swelling Index of Polymers

Swelling studies was conducted on methyl cellulose and it was found that methyl cellulose has got swelling ratio of 4.

Initial Stage Final Stage

Fig. 1 Swelling behaviour of methyl cellulose

3. Compatibility studies using FT/IR Spectrometer

By using shimadzu FT/IR spectrometer the compatibility studies between the drug and the polymer were carried out ( Table: 1) and the spectras obtained are as shown in the Fig.2-4. It was found that the IR spectra obtained from the physical mixture of drug and polymer were matching with the spectra of pure drug. There was no disappearance or appearance of any characteristic peaks. All the major peaks in spectra of mixture of drug and polymer were matching with the standard peak values of the drug. Therefore it was confirmed that no chemical interaction between drug and polymer exist and hence the polymer were used for the further formulation of the patches.

Chlorpheniramine maleate was designed as a Transdermal patch by developing around 10 formulations using methyl cellulose as polymer followed by the preformulation studies. DBP was used as plasticizer. Patches prepared were subjected for various physico-chemical evaluations like appearance, patch thickness, drug content, moisture content, moisture uptake and swelling index, in vitro dug release and permeation studies. Composition of various patches prepared are given in Table: 2.

Various evaluations of the patches were done and the results were given in the Table: 3.

5. Physical appearance

The patches formed were flexible, smooth and homogeneous.

6. Thickness of the patch

In case of formulations M1-M10 the patch thickness varied from 0.137-0.191 nm with highest patch thickness of 0.191 nm in case of M10 and the lowest patch thickness of 0.137nm in case of M1.

Table: 1 FTIR interpretation of CPM and mixture of CPM and polymers

Peaks for functional group assignment	Standard CPM	(a) CPM	(b) CPM + Methyl cellulose	(c) CPM + PVP + Methyl cellulose
C-H Stretching aromatic vibration	~ 3030	3026.41	3074.63	3028.34
C-H Stretching, alkane	2962-2853	2968.55	2963.72	2961.8
C-C multiple bond stretching , aromatic	~1450	1459.2	1447.4	1445.7
COOH carboxylate Anion stretching	1400-1300	1384.94	1378.62	1386.86
C-N vibration, aromatic 2°amine	1350-1250	1194.94	1208.3	1193.88
C-N Vibration, aliphatic 3°amine	1220-1020	1091.75	1093.16	1091.75
CH=CH bending, alkene	995-985	1013.63	1017.22	1013.63
C-Cl Vibration, aliphatic	800-600	865.1	871.3	865.1
C-H bending, aromatic adjacent hydrogen atom	~780s	742.1	726.8	752.26

Table: 2 Formulation of CPM transdermal patches made with methyl cellulose

Components	M₁	M₂	M₃	M₄	M₅	M₆	M₇	M₈	M₉	M₁₀
Methyl Cellulose	4%	4%	4%	3%	5%	4%	4%	4%	4%	4%
PVP	-	20%	20%	20%	20%	-	20%	10%	10%	10%
DBP	-	-	10%	10%	10%	10%	-	10%	15%	10%
CPM(mg)	16	16	16	16	16	16	16	16	16	16

Table: 3 Evaluation of CPM transdermal patches made with methyl cellulose.

Components	M₁	M₂	M₃	M₄	M₅	M₆	M₇	M₈	M₉	M₁₀
Path thickness	0.137	0.144	0.152	0.158	0.1655	0.1711	0.185	0.189	0.1898	0.191
% Moisture content	2.15	3.1	4	3.6	4.09	2.73	3.88	3.125	3.49	3.05
% Moisture uptake	15.21	20.47	22.54	26.54	21.55	17.12	24.63	22.36	23.55	21.42
% Swelling index of patches	17.164	19.14	23.39	20.47	23.92	19.44	19.72	18.84	19.41	18.55
% Drug content	84.2	86.3	98.43	90.2	90.62	98.75	97.65	96.87	93.75	96.87

Table: 4 In vitro dissolution of CPM transdermal patches developed from methyl cellulose.

Optimized Formulation	Percentage release of drug from CPM transdermal patch at
Optimized Formulation	1hr (%)	2hr (%)	3hr (%)	4hr (%)	5hr (%)	6hr (%)	7hr (%)	8hr (%)	24hr (%)
M3	6	14	24	34	39	50	56	60	90
M5	4	10	19	29	35	43	49	55	83
M6	7	12	24	32	37	48	54	59	88
M7	6	13	23	31	39	47	52	58	86
M8	10	16	28	38	40	56	61	64	92
M9	8	17	26	35	43	55	60	67	93
M10	9	15	27	36	41	57	59	62	91

Table: 5 Drug release kinetics of CPM transdermal patches developed from methyl cellulose.

Optimized Formulation	Zero order R²	First order R²	Higuchi's kinetics R²	Korsemeyer kinetics R²
M3	0.8070	0.9872	0.9404	0.9192
M5	0.8182	0.9718	0.9453	0.9122
M6	0.8140	0.9823	0.9416	0.9268
M7	0.8112	0.9774	0.9430	0.9237
M8	0.7783	0.9824	0.9183	0.9264
M9	0.7775	0.9854	0.9189	0.9250
M10	0.7760	0.9794	0.9189	0.9227

The release kinetics profile of the formulations made with methyl cellulose (M3, M5, M6, M7, M8, M9 and M10) were found to obey first order kinetics.

Table: 6 In vitro permeation of CPM transdermal patches developed with methyl cellulose

Optimized Formulation	Percentage of drug permeated from CPM transdermal patches at
Optimized Formulation	1hr (%)	2hr (%)	3hr (%)	4hr (%)	5hr (%)	6hr (%)	7hr (%)	8hr (%)	24hr (%)
M3	8	14	24	34	40	48	56	59	76
M5	6	13	21	31	37	43	49	56	69
M6	9	13	24	32	39	47	54	58	72
M7	8	12	23	29	35	41	50	56	71
M8	12	16	26	32	39	55	59	62	78
M9	9	15	23	35	41	55	60	64	80
M10	10	19	27	36	43	48	56	60	78

Table: 7 Stability study data of CPM transdermal patches made with methyl cellulose.

Formulation code	% Drug released at 24 hr	% Drug permeated at 24 hr
M8	88	77
M9	89	78
M10	89	76

Fig. 5 In vitro dissolution of CPM transdermal patches developed from methyl cellulose.

Fig. 6 In vitro permeation of CPM transdermal patches developed with methyl cellulose.

7. Drug content of the patch:

In case of formulations from M1-M10 the drug content ranged between 84.2-98.75%. The highest drug content was seen in case of M6 with 98.75% and the lowest drug content was seen in case of M1.

8. Moisture content of the patch:

In case of formulations of patches M1-M10 the moisture content varied from 2.15-4.09%. The highest was seen in case of M5 and the lowest moisture content was seen in case of M1.

9. Moisture uptake of the patch:

The moisture uptake varied from 15.21-26.54% in case of formulations of patches M1-M10. The highest was seen in case of M4 and the lowest moisture uptake was seen in case of M1.

10. Swelling index of patch:

Swelling index of the patches varied from 17.16- 23.92% in case of formulations M1-M10. The highest was found in case of M5 and the lowest was found in case of M1.

11. In vitro dissolution study of the patch:

The optimized formulations M3, M5, M6, M7, M8, M9, M10 of CPM transdermal patches made with methyl cellulose are subjected to in vitro dissolution studies and are as reported in Table: 4 and Fig.5.

In case of patches developed from methyl cellulose as polymer; M9 showed highest cumulative percentage of drug release of 93% and M5 showed the lowest cumulative percentage of drug release of 83% among the formulations from M3-M10. Followed by M9, the cumulative percentage of drug release decreased in the order of M8>M10>M3>M6>M7 with 92%>91%>90%>88%>86% respectively. It was observed that, with the decrease in concentration of methyl cellulose and increase in concentration of the plasticizer DBP along with an optimum concentration of the copolymer PVP, the formulation showed an increase in cumulative percentage of drug release.

Drug release kinetics:

The optimized formulations of CPM transdermal patches made with methyl cellulose (M3, M5, M6, M7, M8, M9 and M10) were subjected to various kinetic studies like first order (log cumulative percentage of drug unreleased verses time), Higuchi's equation (cumulative percentage of drug unreleased verses square root of time,1962) and Korsemeyer's (log cumulative percentage of drug released verses log of time,1983) along with a zero order (cumulative percentage of drug released verses time) pattern and are reported in Table: 5.

12. In vitro permeation studies using Franz Diffusion cell:

The optimized formulations M3, M5, M6, M7, M8, M9, M10 of CPM transdermal patches made with methyl cellulose are subjected to in vitro permeation studies and are as reported in Table: 6 and Fig.6.

In case of patches developed from methyl cellulose as polymer; M9 showed highest cumulative percentage of drug permeation of 80% and M5 showed the lowest cumulative percentage of drug permeation of 69% among the formulations from M3-M10. Followed by M9, the cumulative percentage of drug permeation decreased in the order of M8 and M10>M3>M6>M7 with 78%>76%>72%>71% respectively. It was observed that, with the decrease in concentration of methyl cellulose and increase in concentration of the plasticizer DBP along with an optimum concentration of the copolymer PVP, the formulation showed an increase in cumulative percentage of drug permeation.

Stability studies:

Among the optimized formulation of patches M8, M9, M10 were tested for stability as per International Conference on Harmonization Guidelines (Q1A(R2), 2003). The formulations were stored at intermediate 30±2˚C/ 65±5% RH test conditions in stability chambers for 6 months. At the third month, the patches were evaluated (Table-7).

CONCLUSION:

The above evaluation of transdermal patches promises that CPM can be developed successfully as transdermal patches as an alternative route of administration fulfilling the objectives of this research work.

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Received on 26.03.2011 Modified on 05.04.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 965-971