DESIGN AND DEVELOPMENT OF MULTIPARTICULATE MINI TABLETS OF VERAPAMIL HYDROCHLORIDE FOR PULSATILE DRUG DELIVERY

Abstract

The objective of the research was to develop and evaluate the multiparticulate pulsatile release minitablets of verapamil hydrochloride for the treatment of hypertension at a desired time to mimic the circadian rhythms and improve the patient compliance. Materials and Methods: Formulation was prepared by CODAS technology. It was designed to initiate the release of verapamil after 4h lag time and reached the therapeutic levels at in the early morning hours, when the blood pressure is at its highest. The core minitablets were prepared by wet granulation process and coated with water insoluble polymer like ethylcellulose along with hydrophilic plasticizer. The formulation attributes were optimized and evaluated the in vitro performance. Results: The in vitro dissolution studies revealed that the coating build-up of ethylcellulose controls the initial lag time and release rate of drug product. Among the formulations (F la) 10% w/w ethylcellulose coated minitablets showed lag time for 4 hr and controlled the release up to 24 hr. The formulation optimization studies illumined the critical attributes like fumaric acid (F2), which modified the microenvironment and improved' the dissolution profile of drug product in phosphate buffer. The optimized formulation (FI a) was compared against the marketed product (CALAPTIN 120 mg SR tablets) and observed that the dissolution behaviöur of the drug product followed first-order kinetics. Conclusion: The outcomes were presumed that the pulsatile release has been accomplished from coated minitablets with a lag time of 4hr, which is reliable with the demands of the chronotherapeutic drug delivery by efficiently control the blood pressure at early morning.

Specification

Description:FIELD OF INVENTION:
[0001] The present invention is to Design and develop multiparticulate mini tablets of Verapamil Hydrochloride for Pulsatile Drug Delivery.

BACKGROUND:
[0002] High blood pressure (Hypertension) is a chronic long-term medical condition that causes cardiovascular diseases with elevated blood pressure in the arteries which majorly occur during early morning.1 Generally, most cardiovascular dosage regimens are according to the cardiac rhythm (24 hr) pattern of blood pressure with morning rise and decline during night time. Chronotherapeutic is a pulsed release system that has been developed, which releases the drug at the desired rate and selected time to mimic the biological rhythms with enhancing therapeutic efficiency, patient compliance and reduced dosing frequency.

[0003] The objective of the research was to develop and evaluate the multiparticulate pulsatile release minitablets of verapamil hydrochloride for the treatment of hypertension at a desired time to mimic the circadian rhythms and improve the patient compliance.

SUMMARY:
[0004] Verapamil hydrochloride (VH) is an antihypertensive drug under BCS class IV calcium channel blocker used for the treatment of high blood pressure, heart arrhythmias, and angina which prevents and relaxes the coronary artery spasm and reduction of oxygen utilization. 90% of the drug is absorbed when administered orally, bioavailability ranges from 20% to 30% due to first-pass metabolism in that portal circulation. Peak plasma concentrations are reached between 1 lo 2 hr after oral administration.

[0005] The mean half-life ranges from 2.8 to 7.4 hr the multiparticulate systems are generally granules, pellets and minitablets. Minitablets are small discrete subunits, containing the drug, with a diameter of 0.05 to 2 mm, which are filled into a hard gelatine capsule. After oral administration, they disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the mucosa by certain irritant drugs, and reduce inter-and interpatient variability. Minitablets has several benefits such as a reliable drug release unfluctuating clinical performance, more flexibility during the development of formulation, and maximum stability on storage.

[0006] In the present investigation, minitablets were developed for pulsatile release pattern, filled in hard gelatine capsules is to lag drug release for 4 hr and to reach therapeutic blood levels in the early morning hours, when the blood pressure is highest and to provide the adequate 24 hr control of blood pressure in patients.

[0007] The formulation and development of a novel multi particulate pulsatile drug delivery system of VH for the treatment of hypertension was successfully done. Based on the results the developed optimized formulation (F1a) released the drug with a lag time of 4 hours after administration at bed time and reaching the blood therapeutic levels in early morning hours, when the blood pressure was high. Consequently, this dosage form regiment provided adequate 24-hour control of blood pressure in patients and followed up the concepts of chrono pharmaceutics, for effectively controlling hypertension at their peak biological time, there by providing relief to the patient.

DESCRIPTION OF FIGURES&TABLES:
[0008] Figure 1: Compressed 2 mm minitablets

[0009] Figure 2: EC coated minitablets

[0010] Figure 3: EC Coated minitablets filled in capsule

[0011] Table 1: Composition of Verapamil HCI minitablets.

[0012] Table 2: Chromatographic Parameters for assay and dissolution method development of verapamil HCI minitablets.

[0013]. Table 4: Results of post-compressed studies on core Verapamil HCI Minitablets.

[0014] Figure 5: Comparative in vitro dissolution profiles of optimized (Fl a) in pH 1.2HCI, pH 4.5 ABS and pH 6.8 PBS.

[0015] Figure 6: Comparative in vitro dissolution profiles of different concentration of fumaric acid in pH 6.8 Phosphate buffer.

[0016] Figure 7: Comparative in vitro dissolution profiles of different concentrations of PEG400 in pH 6.8 phosphate buffer.
[0017] Figure 8: Comparative in vitro dissolution profiles of different levels of povidone K30 in pH 6.8 Phosphate buffer.

[0018] Figure 9: Comparative in vitro dissolution profiles of different concen1ration of magnesium stearate in pH 6.8 PBS.

[0019] Figure 10: Comparative in vitro dissolution profiles of optimized formulation.

[0020] Figure 11: In vitro dissolution profile of stability studies of optimized formulation (F1a) at 40±2°C of 1 and 3 months in pH6.8 PBS.

DETAILED DESCRIPTION:
[0021] Formulation was prepared by CODAS technology. It was designed to initiate the release of verapamil after 4h lag time and reached the therapeutic levels at in the early morning hours, when the blood pressure is at its highest. The core minitablets were prepared by wet granulation process and coated with water insoluble polymer like ethyl cellulose along with hydrophilic plasticizer. Preparation of verapamil HCl minitablets: the core minitablets were fabricated the wet granulation process. 11, c weighed quantity of VH, MCC (Avicel PH 101) were granulated with 5% w/w fumaric acid solution and followed by 20% w/w PVP K30 in isopropyl alcohol which is dried at 40°C in an oven and mixed with MCC (Avicel PH102) which was sifted via #30 and lubricated with sifted magnetism steerable. the resulting granules were compressed into minitablets with a 2 mm multi-tip punch (Figure l). The composition of verapamil HCl minitablets (VHMTs) is as shown in (Table 1).

[0022] Coating of verapamil HCl minitablets: the core minitablets were coated with the ethyl cellulose (strength of 2% w/w) prepared in the ratio of 60:40% w/w of isopropyl alcohol, dichloromethane, and 5% w/w PEG400. The resulting coating solution was sprayed onto the minitablets with 0.01 g/mL of spray rate with rotating speed 30RPM at 30 to 40°C inlet temperature and continued the coating until the weight build-up achieved up to 5%, 10%, 15%w/w (Figure 2) and the coated minitablets (Around 28 minitablets) were filled in size'' gelatine capsules is equivalent to core tablet weight (Figure 3).

[0023] Analytical methods for Verapamil HCI minitablets Method for assay: The mobile phase was prepared by a combination of pH 3.0 triethylamine phosphate buffer, acetonitrile, mid methanol iJ1 the ratio of 60:24:16% v/v and filtered with vacuum through a 0.45 µm membrane filter and degassed in a so nicator for about 5 min. results are expressed as (Mean± SD). CI and HR were computed from the mean values of BD and TD.

[0024] post-compression studies: The post-compression characteristics of compressed minitablets were evaluated like thickness (mm), crushing force (kg/cm2), friability, and mass variation. For the assay, minitablets weighed corresponding to 120 mg of VH and transferred into 100 mL of water: methanol and ultrasonicated for 15 min. All tests are carried out in triplicate (n=3) and the results are expressed as (Mean± SD).

[0025] In vitro dissolution studies: In vitro drug release studies were performed using USP apparatus II (Paddle), 50 rpm at 37 ± 0.5°C for 24 hr. Accurately weighed minitablets equivalent to label claim was taken into a capsule fitted in sinker size "0" and transferred into the dissolution vessel with 900 mL of pH 6.8 (PBS) and collected.

[0026] In vitro release kinetic studies of optimized formulation: The drug release data obtained after in vitro dissolution studies were fitted into various order kinetics: Zero-order (Cum. % drug release vs. time), First order (Log cum. % drug undissolved vs. time), Higt1'-hi's (Cum.% drug release vs. time), and Korsmeyer­ Peppas (Log cum. % drug released vs. Log time) to comprehend the kinetics and mechanism of drug release from minitablets.

[0027] Optimization studies: the formulation attributes like the concentration of fumaric acid, magnesium stearate, and concentration of coating build­ up on minitablets were studied by one factor at a time method and evaluated by measuring the critical quality attributes like dissolution profile of drug product in pH 6.8 phosphate buffer. 111e justification for the selection of formulation attributes is as below.

[0028] Furnari acid is an organic acid that acts as a pH modifier, changes the microenvironment around the drug substance in the product, and improves the solubility of the drug substance. Hence, the concentration of fumaric acid was selected as a critical formulation and studied the effected in formulation (Fla) with and without (F2) fumaric acid. Polyvinyl pyrrolidine (PVP K30) is a binder, which imparts the cohesive properties between the blend particles and improves the rheological properties of dried granules, and also improve. the hardness of minitablets.1l1e change in concentration of PVP K30 impacts the rheological properties of dried granules and the release profile of drug product. Hence defining concentration levels like 2.26% w/w (F3), 3.26% w/w (Fla) and 4.26% w/w (F4) were studied.

[0029] Ethyl cellulose is a hydrophobic controlled release polymer. The change in its concentration modifies the dissolution profile of the drug product. Hence the different percentage coatings build­ up with 5% w/w (Fl), 10% w/w (Fla), and 15% w/w (Flb) were studied. PEG 400 is used as a water-soluble plasticizer. The change in concentration of plasticizer impacts on the coating film nature and dissolution profile of the drug product. Hence different concentration like 5% w/w (Fl b), 3% w/w (F7) and without (F8) PEG400 was studied.

[0030] Stability studies of the optimized formulation: The final optimized formula (FIa) of minitablets were filled in gelatine capsule Size "l" and packed in a HOPE bottle and placed at temperature 40±2°C up to 3 months. The stability samples of I" month and 3rd month, capsules were subjected to assay and in vitro dissolution studies in pH 6.8 phosphate buffer (PBS). , Claims:Claims:
I/We Claim:
1.A process of preparing verapamil HCI minitablets, comprising:
a wet granulation process;
a Verapamil hydrochloride (VH);
a fumaric acid solution
the Verapamil hydrochloride (VH) was granulated with 5% w/w of the fumaric acid solution;
a polyvinylpyrrolidone (PVP K30);
an isopropyl alcohol;
whereby 20% w/w of the polyvinylpyrrolidone (PVP K30) is added into the isopropyl alcohol;
the mixture is dried at 400C in an oven and mixed with microcrystalline cellulose (MCC);
whereby lubricated with sifted magnesium stearate;
the resulting granules were compressed into minitablets with a 2 mm multi-tip punch;
an ethyl cellulose;
the minitablets were coated with ethyl cellulose of 2% w/w and prepared in the ratio of 60:40% w/w of isopropyl alcohol, dichloromethane and 5% w/w PEG400;
the resulting coating solution was sprayed onto the minitablets with 0.01 g/mL of spray rate with rotating speed 30RPM at 30 to 400C inlet temperature;
the coating is continued until the weight build-up achieved up to 5%, 10%, 15%w/w; and
the coated minitablets were filled in size "1" gelatine capsules is equivalent to core table weight.

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