Over the past 30 years, as the expense and complications involved in marketing now drug entities have increase, with concomitant recognition of the therapeutic advantages of controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug delivery systems. The attractiveness of these dosage forms is due to awareness to toxicity and ineffectiveness of drugs when administered or applied by conventional method in the form of tablets, capsules, injections, ointments etc. usually conventional dosage form produces wide ranging fluctuation in drug concentration in the blood stream and tissues with consequent undesirable toxicity and poor efficiency. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of controlled delivery system. The goal in designing sustained or controlled delivery system is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery. So, controlled release dosage form is a dosage form that release one or more drugs continuously in predetermined pattern for a fixed period of time, either systematically or to a specified target organ, controlled release dosage forms provide a better control of pharma drug levels, less dosage frequency, less side effect, increased efficacy and constant delivery.³ Sustained release systems include any drug delivery system that achieves slow, release of drug over an extended period of time. ⁴

As already mentioned, conventional dosage forms include solutions, capsules, tablets, emulsions etc. These dosage forms can be considered to release their active ingredients into an absorption pool immediately.

Kr Ka Ke

Dosage form ----- Absorption pool ----- Target area ------
Drug release absorption elimination

The absorption pool represents a solution of drug at the site of absorption

Where

Kr = First order rate constant for drug release

Ka = First order rate constant for drug absorption

Ke = First order rate constant for overall drug elimination

For immediate release dosage forms Ke >>> Ka or alternatively absorption of drug across a biological membrane is the rate-limiting step in delivery of the drug to its target area.

For non-immediate release dosage forms, Kr <<< Ka that is, release of drug from the dosage form is the rate limiting step. This cause the above kinetics scheme to reduce to

Kr Ke

Dosage form ----------- Target area ----------
Drug release elimination

Thus, the effort to develop a delivery system that releases drug slowly must be directed primarily at altering the release rate by affecting the value of Kr.^{2, 5, 6}. In pharmaceutical practice several approaches exist for administration of drugs to the patients. If the drug is given in conventional dosage form, it has to be administrated several times to produce desired therapeutic effect. Because of frequent closing fluctuation in plasma drug level occurs. The pronounced fluctuation resulting from the conventional drug administration are likely to yield period of therapeutic effects, when the concentration falls below the minimum therapeutic level. Drug concentration can be controlled within the narrow therapeutic range by the use of sustained release systems, which will minimize the severity of side effects. Tolperisone hydrochloride is a centrally acting muscle relaxant that has used for symptomatic treatment of spasticity and muscle pain, with half-life of 2.5-3 hours and requires multiple daily doses to maintain adequate plasma concentrations, so it is selected to prepare a sustained release tablets. The objective of this present study to develop a competitive sustained release tablets of Tolperisone Hydrochloride which releases the drug in a sustained manner over a period of 24 hours, by using different polymer and study on there effect on release pattern.^6,7.

2. MATERIALS AND METHODS:

2.1 Materials:

Tolperisone HCl (Active), HPMC K – 100 (Polymer), Ethyl Cellulose (Polymer), Carbopol – 971 (Polymer), Starch (Binder), Lactose (Diluent), Aerosil (Glident), Talc (Adsorbent), Methylene dichloride (Coating agent).

Electronic balance (Shimadzu corporation An220), Tray Dryer (Erweka Pvt. Ltd), Coating Machine (Erweka Pvt. Ltd), Dissolution apparatus (USP) (Labindia Pvt. Ltd), Compression machine (Anchor Mark Pvt. Ltd), Tablet Hardness Tester (Vankel Ltd K200), Friability test apparatus (Electro Lab Pvt. Ltd., EF-2 USP), Ultraviolet visible spectrophotometer (Shimadzu Corporation UV – 1700

2.2 METHODS:

2.2.1 Preformulation Study:

Drug Excipient Compatibility Study:

Compatibility studies were conducted to investigate and predict physicochemical interaction between drug substance and excipients and therefore to select suitability of chemically compatible excipients.

2.2.2 Formulation Development of Tolperisone Hydrochloride sustained release tablet

Procedure

It was planned to take different trials with different polymers, and using the polymers in internal phase (Dry mixing stage) and external phase (lubrication stage), which will help the dosage from provide sustained release of Tolperisone hydrochloride in the GIT. Mainly formulation is planned to be made by wet granulation technique and film coated using instacoat universal. (Refer Table-1)

Table No. 1: Composition of TSR-01 to TSR-05 of Tolperisone hydrochloride SR tablets

Ingredients	Formulation No.
Ingredients	TSR -01(mg)	TSR -02 (mg)	TSR -03 (mg)	TSR -04 (mg)	TSR -05 (mg)
Tolperisone HCl	450	450	450	450	450
HMPC K-100	250	250	300	300	300
Ethyl Cellulose	40	50	50	50	25
Carbopol-971 P	-	-	50	50	75
Lactose	100	100	-	-	-
Purified Water	qs	-	-	-	-
Starch	20	-	-	-	-
Isopropyl Alcohol	-	qs	qs	qs	qs
Talc	-	8	8	8	8
Aerosil	8	8	8	8	8
Mg. Stearate	2	4	4	4	4

Table No. 2: Physical observation of compatibility study

Drug and Excipient Ratio 1: 1	Observation
Drug and Excipient Ratio 1: 1	Initial	30^oC/65%RH after 30 days	40^oC/75% RH after 30 days	Result
Tolperisone Hydrochloride	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + HPMC K-100	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolpersone HCl + Ethyl Cellulose	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Carbopol-971 P	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + IPA	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Aerosil	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + mg. sterate	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Lactose	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Starch	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Instacoat (universal)	White to off white powder	White to off white powder	White to off white powder	Compatible
Tolperisone HCl + Methylene dichloride	White to off white powder	White to off white powder	White to off white powder	Compatible

Fig. No. 01: Drug release profile of SR Tablets (TSR– 01 to TSR- 05)

Formulation TSR- 01 TO TSR 05 of sustained release tablets of drug Tolperisone HCl:

Formulation Steps¹⁴:

Step 1: dispensing of active ingredients and excipients.

Equipments used: 6 dispensing balance and calibrated balance

Process: Dispense all the materials in stage wise sequence as per dispensing sheet.

Record the weight and label the dispensed materials.

Step 2: Sifting and dry mixing

Equipments used: Sieve, 60#, and vibrosifter

Process: Shift all row materials through 60#. Mix tolperisone HCl, HPMC, K-100 and Lactose in geometric proportion and pass through 60#.

Step 3: Preparation of binder solution

Equipments used: Dry beaker, dry spatula, dry glass rod, heating mantle.

Process: Took purified water in a beaker and starch and stir with glass rod, heated at 60 degree calcius with continuous stirring up to made starch slurry.

Step 4: Mixing and wet granulation

Equipment used: Rapid mixer granulator

Process: Temperature (NMT- 25^oC), Humidity (RH – NMT – 55%).

Dry Mixing: Added sifted material from step 2 and mix the ingredients in RMG at slow speed of impeller and chopper in off position for 15 minutes.

Wet granulation: Added the binder solution from step 2 in above dry mix by opening the valve on planetary mixer bowl. After completing addition of binder solution started the impeller and chopper at slow speed and continue the wet granulation for appropriate time.

Table No. 03: Drug release profile of SR Tablets FROM TSR- 01 to TSR- 05

Time (Hrs)	TSR-01	TSR-02	TSR-03	TSR-04	TSR-05
0.5	20	17	15	24	16
1	25	35	19	39	18
2	32	43	32	53	33
4	43	59	40	66	41
6	66	67	50	71	54
8	78	75	58	79	69
10	83	80	64	84	78
12	85	84	73	95	83
16	81	88	88	98	85
20	79	87	85	99	88
24	76	84	85	96	99

Step 5: drying and LOD checking

Equipment used: Fluid bed dryer, IR Moisture balance.

Process: Temperature (NMT – 25^oC), Humidity (RH – NMT 55%)

Dried the granules in FBD with maintained temperature and humidity. Then set the shaking interval to after every 10 minutes and shaking time is 01 minute. Remove the FBD bowl with the dried granules from the FBD. Checked the LOD value of dried granules on IR moisture balance.

Step 6: Final sifting and sieving

Equipments used: Sieve 20# and 2.0mm mesh, vibrosifter and multimill.

Process: Shifted the dried granules from step 5 through 20# sieve in vibrosifter. Oversized granules were passed through multimill by 2.0mm mesh.

Step 7: Lubrication and blending

Equipments used: Sieve 60# multicone blender.

Process: Sifted the ethyl cellulose, Aerosil, by sieve 60# and mixed with step 6 in multicone blender for 10 minutes, then added magnesium stearate.

Step 8: Compression

Equipment used: Compression machine.

Process: Compress the lubricated granules using 13mm round shape punches and collected uncoated tablets in storage bin.

Step 9: Preparation of coating solution

Equipments used: Colloidal mill, storage bin, and stainless steel vessels.

Process: Taken isopropyl alcohol (IPA) in colloidal mill, added insta-coat universal (HPMC + PEG + Talc + Titanium dioxide) slowely with continuous stirring to 10 minutes. Added methylene dichloride in this solution and colloid for next 10 minutes. Filter the solution through 200-mesh nylon cloth into coating solution tank.

Step 10: Coating of tablet

Equipment used: Coating pan

Process: Loaded the uncoated tablets of tolperisone hydrochloride from step 8 of in coating pan. Sprayed the coating solution from step 9 on tablets with the help of spray gun.

Formulation steps were similar in all the compostions from TSR 01 to TSR 05. Details of composition given in below table.

2.2.3 In-Vitro Dissolution Study of Tolperisone hydrochloride SR Tablets¹³

Instrument (BY UV-VIS spectrophotometer) at 261 nm

Dissolution medium:

1- Simulated Gastric Fluid (SGF)

Dissolve 2.0 g of sodium chloride in water. Add 7.0 ml of hydrochloric acid and sufficient water to make 100.0 ml. This test solution has a pH of about 1.2.

2- Simulated Intestinal Fluid (SIF)

Dissolve 6.8 g of monobasic potassium phosphate in 250.0 ml of water, mix and add 77.0 ml of 0.2 N sodium hydroxide and 500 ml water. Adjust the resulting solution with either 0.2 N sodium hydroxide or 0.2 N hydrochloric acid to a pH of 6.8 ± 1. Dilute with water to 1000.0 ml. Take 900 ml dissolution medium in each jar, add one tablet to each jar and run as per following:

Temperature: 37.0 ˚C + 2

RPM: 100

Total time 24.0 hours:

1- SGF- 900.0 ml for first 2h.

2- SIF till 24 h

Sampling Time:

SGF 0.5, 1.0, 2.0, SIF- 4.0, 6.0, 8.0, 10.0, 12.0, 16.0, 20.0, 24.0

Sample Preparation:

Taken filter solution 0.2 ml diluted in 10.0 ml of disso media.

Standard Preparation:

Weigh 50.0mg of tolperisone hydrochloride dissolve in 50.0 ml of disso media, in this solution taken 1.0 ml diluted with 100.0 ml of disso media.

Calculation for Tolperisone:

= Abs of Spl. x 50.0. x 1.0 x 900 x 10 x Potency of Standard

Abs of Std. x 50 x 100 x 1 x 0.2 x 450

3.0 Result and Discussion:

The drug and excipient, which is selected to form the sustained release tablet, were tasted for compatibility study. The drug should be kept individually and in combination with excipient in 1:1 ratio in closed vial for 30 day’s and found Drug and excipient of all in combination are compatible with each other in following manner.

CONCLUSION:

Ø From TSR- 01 more than 85% of the drug released in within 12 hours after that the percentage of drug release was decreased due to amount of polymer and moisture content. So, the drug release retardant by increasing polymer.

Ø Increasing the lubricant for good flow property in next trial. Sticking problem occurred in the first trials this was due to higher moisture content, the next trial would be tried with non-aqueous granulation

Ø From TSR- 02 more than 81% drug release is within 16 hours after that the percentage of drug release was decreased due to less amount of polymer. So the drug release retardant polymer percentage was increased.

Ø From TSR- 03, 88% drug release is within 20 hours after that percentage of drug release was decreased. In order to achieve desired drug release steps has to be taken in the subsequent trial.

Ø From TSR- 04, Drug release was improved satisfactory than previous trial. This may be due to addition of low associate HPMC K-100 with the combination of Ethyl cellulose and Carbopol-971 P in dry mixing. But the individual linearity of tablet, in vitro dissolution is not satisfactory hence it has to be improved in the next trial.

Ø From TSR- 05, this batch gave 33% drug release at 2 hours and 69% drug release of 8 hours and 98% drug release at 24 hours. In this trial all physicochemical parameters are found to be within the limit was observed.

Thus the polymers concentration and excipients concentration in this formulation was optimized.

ACKNOWLEDGEMENT:

Authors are very thankful to Principal, Institute of Pharmacy, RITEE, Raipur for providing adequate facilities for research work.

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Received on 25.06.2011

Accepted on 15.08.2011

Research Journal of Pharmaceutical Dosage Forms and Technology. 3(5): Sept.-Oct. 2011, 220-224

Ingredients

Observation