Formulation and Evaluation of Oral Controlled Release Tablets of Milnacipran Hydrochloride

 

Dr Y. Krishna Reddy*, V. Bharani

 

Department of Pharmaceutics, Nalanda College of Pharmacy, Jawaharlal Nehru Technological University, Hyderabad, Telangana.

 

ABSTRACT:

The present investigation is aimed at formulating and evaluating controlled release tablets of Milnacipran HCL using different grades of HPMC polymers such asHPMC K100M, HPMC K15M and HPMC K4M. The controlled release tablets were prepared by direct compression method. The powders for tableting were evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index and Hausner’s ratio etc. The powder blend showed satisfactory flow properties. The tablets were subjected to thickness, average weight, drug content, hardness, friability and in-vitro release studies. All the formulations showed good results which were compliance with Pharmacopoeial standards. In-vitro drug release studies were carried out using USP dissolution apparatus type II paddle type at 50 rpm with 900 ml phosphate buffer solutions of pH 6.8, maintained at 37±0.5°C. The controlled release tablets containing 1:3 ratio Hydroxypropylmethylcellulose (HPMC K100M) (Formulation M3) were show good initial release and extended the release up to 12 hours. The release data for formulation M3 was fitted to various mathematical models like zero order, first order, Krosmeyer Peppas and Higuchi model. It was observed that drug follows Peppas release kinetics mechanism.

 

 

 

INTRODUCTION:^1-9

Controlled release tablets are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to take three or four times daily to achieve the same therapeutic effect. The advantage of administering a single dose of a drug that is released over an extended period of time to maintain a near-constant or uniform blood levelof a drug often translates into better patient compliance, as well as enhanced clinical efficacyof the drug for its intended use.

 

The first Controlled release tablets were made by Howard Press in New Jersy in the early 1950's. The first tablets released under his process patent were called 'Nitroglyn' and made under license by Key Corp. in Florida.

 

Controlled release, prolonged release, modified release, extended release or depot formulations are terms used to identify drug delivery systems that are designed to achieve or extend therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.

 

The goal in designing Controlled or Controlled delivery systems 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 systemically or to a specified target organ.

 

Controlled release dosage forms provide a better control of plasma drug levels, less dosage frequency, less side effect, increased efficacy and constant delivery. There are certain considerations for the preparation of extended release formulations:

·       If the active compound has a long half-life, it is Controlled on its own,

·       If the pharmacological activity of the active is not directly related to its blood levels,

·       If the absorption of the drug involves an active transport and

·       If the active compound has very short half-life then it would require a large amount of drug to maintain a prolonged effective dose.

 

The above factors need serious review prior to design.

 

RATIONALE FOR EXTENDED RELEASE DOSAGE FORMS^10-12:

Some drugs are inherently long lasting and require only once-a-day oral dosing to sustain adequate drug blood levels and the desired therapeutic effect. These drugs are formulated in the conventional manner in immediate release dosage forms. However, many other drugs are not inherently long lasting and require multiple daily dosing to achieve the desired therapeutic results. Multiple daily dosing is inconvenient for the patient and can result in missed doses, made up doses, and noncompliance with the regimen. When conventional immediate-release dosage forms are taken on schedule and more than once daily, they cause sequential therapeutic blood level peaks and valleys (troughs) associated with the taking of each dose. However, when doses are not administered on schedule, the resulting peaks and valleys reflect less than optimum drug therapy. For example, if doses are administered too frequently, minimum toxic concentrations of drug may be reached, with toxic side effects resulting. If doses are missed, periods of sub therapeutic drug blood levels or those below the minimum effective concentration may result, with no benefit to the patient. Extended-release tablets and capsules are commonly taken only once or twice daily, compared with counterpart conventional forms that may have to be taken three or four times daily to achieve the same therapeutic effect. Typically, extended-release products provide an immediate release of drug that promptly produces the desired therapeutic effect, followed by gradual release of additional amounts of drug to maintain this effect over a predetermined period (Fig.1).

 The Controlled plasma drug levels provided by extended-release products oftentimes eliminate the need for night dosing, which benefits not only the patient but the caregiver as well.

 

Figure1: Hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of Controlled and controlled delivery formulations.

 

Drawbacks of Conventional Dosage Forms¹³:

1.   Poor patient compliance, increased chances of missing the dose of a drug with short half-life for which frequent administration is necessary.

2. A typical peak-valley plasma concentration time profile is obtained which makes attainment of steady-state condition difficult.

3.   The fluctuations in drug levels may lead to precipitation of adverse effects especially of a drug with small Therapeutic Index (TI) whenever over medication occur.

 

AIM OF WORK:

The main aim of the present study is to Formulation and in vitro evaluation of controlled release tablets Milnacipran HCLby using different polymers.

 

OBJECTIVES OF THE WORK:

To design of controlled release dosage form of Milnacipran HCL that will help in releasingonly small quantities of drug over a prolonged period of time.

·       To study the effect of type of polymers and polymer concentration on release profiles of controlled release Milnacipran HCLformulations.

·       To arrive at better formulation based on comparison amongst the studied ones.

 

MATERIALS AND METHOD:

Milnacipran HCL Procured from Torrent Pharmaceuticals, Bhatt, India.Provided by SURA LABS, Dilsukhnagar, Hyderabad. HPMCK100M purchased from Yarrow chemicals (Mumbai, India). HPMC K15M was purchased from SD Fine Chem. Ltd. (Mumbai, India). HPMCK4M purchased from Arvind Remedies Ltd, Tamil nadu, India. PVP K 30, Magnesium stearate and Talc purchased from Merck Specialities Pvt Ltd, Mumbai, India. MCC purchased from Chemdyes Corporation (Ahmedabad, India).

 

METHODOLOGY

Table1: Formulation composition for tablets

INGREDIENTS (MG)	FORMULATION CODES
	M1	M2	M3	M4	M5	M6	M7	M8	M9
Milnacipran HCL	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
HPMCK100M	8	16	24	-	-	-	-	-	-
HPMC K15M	-	-	-	8	16	24	-	-	-
HPMCK4M	-	-	-	-	-	-	8	16	24
PVP K 30	8	8	8	8	8	8	8	8	8
MCC	62.5	54.5	46.5	62.5	54.5	46.5	62.5	54.5	46.5
Magnesium stearate	5	5	5	5	5	5	5	5	5
Talc	4	4	4	4	4	4	4	4	4
Total weight	100	100	100	100	100	100	100	100	100

 

RESULTS AND DISCUSSION:

Analytical Method:

Graphs of Milnacipran HCL were taken in 0.1N HCL and in pH 6.8 phosphate buffer at 215 nm and 220 nm respectively.

 

Table2: Observations for graph of Milnacipran HCL in 0.1N HCL

Concentration (µg/ml)	Absorbance
0	0
2	0.118
4	0.235
6	0.347
8	0.471
10	0.596

 

Fig2: Standard curve of Milnacipran HCL

Table3: Standard graph values of Milnacipran HCL at 220nm in pH 6.8 phosphate buffer

Concentration (µg/ml)	Absorbance
0	0
2	0.126
4	0.235
6	0.348
8	0.456
10	0.555

 

Fig3: Standard curve of Milnacipran HCL

 

Preformulation parameters of powder blend

Table4: Pre-formulation parameters of Core blend

Formulation code	Angle of repose (Ө)	Bulk density (gm/cm3)	Tapped density (gm/cm3)	Carr’s index (%)	Hausner’s ratio
M1	26.52±0.03	0.431±0.089	0.518±0.057 1	16.80±0.58	1.20±0.063
M2	26.78±0.84	0.423±0.035	0.538±0.028	21.38±0.66	1.27±0.034
M3	26.16±0.72	0.418±0.021	0.533±0.026	21.58±0.84	1.28±0.073
M4	25.36±0.73	0.445±0.018	0.528±0.012	15.72±0.75	1.19±0.035
M5	27.48±0.67	0.436±0.067	0.539±0.09	19.10±0.12	1.23±0.088
M6	28.24±0.46	0.467±0.052	0.536±0.012	12.87±0.88	1.15±0.067
M7	25.78±0.26	0.452±0.033	0.514±0.090	12.06±0.45	1.14±0.056
M8	26.69±0.56	0.473±0.025	0.525±0.014	9.90±0.76	1.11±0.023
M9	25.83±0.13	0.426±0.032	0.519±0.040	17.92±0.55	1.22±0.022

All the values represent n=3

 

Table 5: In vitro quality control parameters for tablets

Formulation codes	Average Weight (mg)	Hardness(kg/cm2)	Friability (%loss)	Thickness (mm)	Drug content (%)
M1	98.24	4.1	0.56	3.59	96.57
M2	95.35	4.6	0.35	3.14	99.32
M3	99.21	4.8	0.78	3.75	95.68
M4	97.86	4.2	0.64	3.92	97.53
M5	98.46	4.0	0.28	3.10	98.65
M6	97.95	4.6	0.60	3.26	99.20
M7	99.58	4.9	0.57	3.40	97.61
M8	98.31	4.5	0.46	3.21	99.71
M9	98.10	4.3	0.51	3.90	98.15

All the parameters such as Average weight, friability, hardness, thickness and drug content were found to be within limits.

 

In vitro drug release studies:

Table6: Dissolution data of Milnacipran HCL tablets

TIME (H)	CUMULATIVE PERCENTAGE OF DRUG RELEASE
	M1	M2	M3	M4	M5	M6	M7	M8	M9
0	0	0	0	0	0	0	0	0	0
0.5	18.48	12.16	06.86	12.85	08.83	5.68	12.50	13.76	17.97
1	26.06	20.02	10.18	21.57	16.72	11.18	16.68	20.53	22.52
2	32.65	28.26	18.69	28.88	23.47	19.35	25.51	26.17	29.79
3	43.15	32.52	25.78	35.80	27.81	23.12	35.25	33.93	37.12
4	58.28	41.57	39.91	46.42	32.77	28.71	41.36	45.82	43.36
5	65.41	56.31	42.27	50.19	38.06	36.43	58.19	51.38	48.68
6	74.13	63.25	48.13	55.96	46.53	42.96	66.95	62.24	54.81
7	81.95	79.25	56.96	61.27	50.77	48.85	74.82	68.16	61.35
8	98.36	83.01	65.33	67.48	56.47	52.32	82.39	76.94	67.97
9		90.19	72.67	71.15	64.18	56.13	89.54	83.29	71.35
10		96.18	77.89	78.96	69.51	63.27	95.15	91.54	79.15
11			86.17	88.73	75.87	67.19		97.31	86.68
12			99.75	93.64	83.15	74.53			97.48

 

Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend has good flow properties. The bulk density of all the formulations was found to be in the range showing that the powder has good flow properties. The tapped density of all the formulations powders has good flow properties. The compressibility index of all the formulations was found to be below 21.58 which show that the powder has good flow properties. All the formulations has shown the Hausner’s ratio below 1.28 indicating the powder has good flow properties.

 

Quality Control Parameters for tablets:

Tablet quality control tests such as weight variation, hardness, friability, thickness and drug release studies in different media were performed on the compression tablet.

 

 

Fig4: Dissolution profile of Milnacipran HCL (M1-M9 formulations)

From the dissolution data it was evident that the formulations prepared with HPMC K100M extract as polymer were retarded the drug release up to 12 hours.

 

Whereas the formulations prepared with lower concentration of HPMC K15Mretarded the drugrelease up to 12 hours in the concentration 8 mg. In higher concentrations the polymer wasunable to retard the drug release up to 12 hours.

 

The formulations prepared with HPMC K4M showed good retardation capacity of drugrelease (97.48%) up to 12 hours in concentration 24mg. whereas low concentrations (8mg, 16mg) not retard the drug release up to 12 hours.

 

Only HPMC K100M, highest concentrations (24mg) retards the drug releaseup to 12 hours and the drug release 99.75% respectively. In this HPMC K100Mreleases the more drug release when comparedto HPMC K15M and HPMC K4M. So M3 Formulation considered as optimised formulation.

 

Hence from the above dissolution data it was concluded that M3 formulation was consideredas optimised formulation because good drugrelease (99.75%) in 12 hours.

 

Drug–Excipient compatability studies

 

Figure 5: FT-TR Spectrum of Milnacipran HCL pure drug

 

 

Figure6: FT-IR Spectrum of Optimised Formulation

 

CONCLUSION:

Development of controlled release tablet of Milnacipran HCLcan be prepared because controlled release formulation can reduce frequency of dose administration, can reduce side effects and improve patient compliance. Therefore in the present study, controlled release tablets of Milnacipran HCL were prepared using synthetic polymersHPMC K100M, HPMC K15M and HPMC K4M by Direct compression method. The active pharmaceutical ingredient Milnacipran HCL was evaluated for its drug polymer compatibility study. Tablet powder blend was subjectedtovarious pre-formulationparameters was found to be acceptable limits. Post compression studies like average weight, Hardness, thickness, friability, drug content was determined as per official requirement of IP indicating a good mechanical resistance of tablets. Based on the in vitro drug release data, the formulation M3 it was concluded as best formulation. The kinetics of drug release was optimized formulation explained by peppas equation. In conclusion thepresent study demonstrated the successful preparation of controlled releasematrix tablet of Milnacipran HCL.

 

 

АCKNOWLEDGEMENT:

The Authors arе thankful to Sura Labs, Dilshukhnagar, Hydеrabad for providing thе necessary facilities for the research work.

 

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