Comparative Assessment of Multi brand and Generic Methylprednisolone tablets marketed in India

Yash Sinha¹, Kuldeep Singh Patel^1,2, Vaishali Rathi¹, Jagdish Chandra Rathi¹, Archana Singh³

¹NRI Institute of Pharmaceutical Sciences, Sajjan Singh Nagar Bhopal, M.P (India) 462021

²Department of Pharmacy, NRI Institute of Research and Technology, Sajjan Singh Nagar Bhopal, M.P (India) 462021

³Govt. Degree College Timrani, M.P, India

*Corresponding Author E-mail: kuldeeppatelrgpv@gmail.com

ABSTRACT:

The research on the topic of branded and generic drug comparison always provides an interesting perspective among pharmacy stakeholders. Physicians often continue to prescribe brand name drugs from the country of origin of the inventor to their patients even when less expensive of same brand drugs that are available in India. A one-sided assertion from drug manufacturers about the equivalent quality of generic drugs with the branded products raises the pros and cons in the community, including the health-care providers. Methylprednisolone (MP) is a corticosteroid hormonal. This drug is commonly used to treat many different conditions such as skin problems, allergic reactions, arthritis, lupus, and other disorders. The comparative pharmacodynamics effect between branded and generic products of MP tablets in the present study was investigated in vivo. The physical parameters i.e. Price variation, weight variation, thickness, hardness, disintegration, dissolutions and chemical assay were considered during the present study. All products had contents compatible within the Pharmacopeias and the dissolution were determined in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) without enzymes for all the drugs showed more than 92% of the API dissolved within 30 minutes. All drugs were approved with regard to tablets pharmacopical parameters are between within the limit. The disintegration time of all samples also proved satisfactory, had completely disintegrated in less than 15 seconds. The SGF indicated over 90% release from eight samples, while it revealed over 81% release in SIF from nine samples out of the above mentioned.

KEYWORDS: Branded drug, Generic, Methylprednisolone, Simulated gastric fluid, Multibranded.

INTRODUCTION:

As India is one of the highest per capita out-of-pocket expenditures’ country, such generics will save a lot of money which can be used for other health issues [1]. In all the countries, use of generic drugs has increased significantly in recent years [2,3]. In 2008, the Government of India, through the Department of Pharmaceuticals, started a new initiative “Jan Aushadhi” (a Hindi word literally translated as “Medicine for People”). This program envisaged making unbranded quality medicines available to poor people in the country at a reasonable and affordable price through retail outlets’ setup with the help of the government. It has taken ownership of setting up Jan Aushadhi stores, which are pharmacies selling only generic name medicines to the extent possible, giving preference to pharmaceutical public sector undertakings too. [4] Until March 15, 2018, 3200 Jan Aushadhi stores were operating in more than 33 states/union territories across India. [5] There are not enough Jan Aushadhi stores, possibly 3200 against more than 8 lakh retail pharmacies in existence, with many rural areas still underserved. [6] The Medical Council of India, in an amendment to the code of conduct for doctors in October 2016, has recommended that every physician should prescribe drugs with generic names legible and he or she shall ensure that there is a rational prescription which promotes the use of generic drugs. [7] In future, the Government of India may bring a legal framework under which doctors will have to prescribe generic medicines to patients. [8] Generic medicines are typically 30%–80% cheaper than originator equivalents. [9] The question raised quite often is “Whether the quality and performance of generic drugs is comparable to the brand drugs?” The proponents of generic drugs claim that they are equally effective as brand or Branded drugs. [10] Subsequent to this claim, the Drugs Technical Advisory Board of India in May 2016 considered amending Rule 65 (11A) of the Drugs and Cosmetics Act, 1940, so that pharmacists can dispense generic name medicines and/or equivalent brands against prescriptions in brand names. However, skeptics have stated that the use of generic drugs may lead to prolongation of illness or even therapeutic failure as the bioavailability (BA) of a generic drug may not be as good as that of the prescribed brand. [11] Hence, the critical issues that affect the quality of generic drugs are purity, potency, stability, and drug release, and these should be controlled within an appropriate limit, range, or distribution to ensure the desired drug quality.

This research on the topic of comparative assesment of multibrand and generic comparison always provides an interesting perspective among pharmacy stakeholders. A one-sided assertion from drug manufacturers about the equivalent quality of generic drugs with the branded products raises the pros and cons in the community, including the health-care providers. The uses of generic drugs, despite varying, are still very popular across the globe. Generic drug prescriptions in the United States are counted 89% and cause only 26% of the total drug cost of the country [12].

Methylprednisolone (MP) is a corticosteroid anti-inflammatory drug classified to glucocorticoid. This drug is commonly used to treat many different conditions such as skin problems, allergic reactions, arthritis, lupus, and other disorders. In Indonesia, the generic products for MP can be priced 10 times cheaper than the Branded drug (Medrol®, produced by Pfizer). This disparity brings a big question on the quality and bioequivalence of drugs, in general, not only to consumers but also to the health-care practitioners [13].

The  bioequivalence  study  between  Branded  and  generic  drugs    is mostly  conducted  by  investigating  the  pharmacokinetic  profile  of the drug molecules in the circulatory system [14]. Another approach that can be useful to compare their quality is by involving the pharmacodynamics aspect of the drug. For MP, we hypothesized that the serum concentration of annexin A1 (AnxA1) would be a good indicator for such purpose. AnxA1 is hormonal protein that is stimulated by MP and considered as the target molecule of corticosteroids in inhibiting the formation of eicosanoids.

The marketing of multisource drug products registered by national drug agencies (Like FDA) in INDIA, with view of improving health care delivery through competitive pricing, has attendant problem of ascertaining their quality and interchange ability [15]

1. Variable clinical responses to drugs presented as generics and batch-to-batch inconsistencies have been reported

2. Such unacceptable trends were exhibited in some drug products.

3. Quality control procedures, which are useful tools for batch-to-batch consistency in manufacturing, should be performed for every drug product. Drugs having more than three generic products require analysis for their biopharmaceutical and chemical equivalency. These methods ensure that any of generic products can be used interchangeably. The observation is that most of generics have much lower shelf prices compared to the Branded products, which raises the issue of the likelihood of unequal product performance. prediction of the in vivo bioavailability of most oral drugs depends on the in vitro dissolution studies because in vitro disintegration tests do not always give good activity.

4. Dissolution testing of drug products plays an important role as a quality control tool to monitor batch-to-batch consistency of drug release from a dosage form and as an in vitro surrogate for in vivo performance [16].

5. The therapeutic efficacy of a drug product intended to be administered by the oral route depends on its rate and extent of absorption by the Gut(git). A comprehensive evaluation, however, involves the determination of uniformity of weight, chemical content, friability, hardness, and disintegration tests along with dissolution rate. Drugs that are chemically and biopharmaceutically equivalent must be identical in strength, quality, and purity. The content uniformity, disintegration, and dissolution rates must be comparable [17].

6. Methylprednisolone now has about ten branded products in the market, and this number is likely to increase with time as manufacturers watch prescriptions for Methylprednisolone increase. In this study, in vitro dissolution techniques were used to ascertain the rate and extent of the active ingredients [18].

Fig. 1 Structure of Methylprednisolone

Fig. 2 2D View

Fig. 3 3D View

MATERIALS AND METHOD:

Materials:

Methylprednisolone having a label strength of 16 mg (Table 1) were purchased from a retail pharmacy in Bhanu Medical Store, Arnav Hospital Bhopal, M.P India. All tests were performed within product expiration dates. Methylprednisolone powder was gift sample by Sun Pharmaeuticals Ltd., India. Freshly prepared distilled water used throughout the work.

Visual Inspection:

The shape, size, and color of the different brands of tablets were examined visually.

Friability Test:

Twenty tablets were weighed and subjected to abrasion using a Jyoti tablet friability tester at 25rev/min.

Hardness Test:

The crushing strength of the tablets was determined using a Mosanto tablet hardness tester (Mosanto).

Weight Variation Test:

The average tablet weight was determined weighing 20 randomly selected and evaluated using an electronic balance (Simadzu Digital balance).

Tablet Disintegration Test:

Tablet disintegration was determined at 37°C using a Jyoti Scientific disintegration testing apparatus.

Dissolution Rate Determination:

Dissolution rates in the simulated body fluids (i.e., SGF and SIF) were determined using a Type -1 dissolution rate testing apparatus using 900mL of medium at 37 ± 0.5°C. The Paddle was rotated at 80rpm. Ten milliliters of sample was drawn at 10-min intervals for 1 h with 10 ml.

The UV absorbance was measured at 287.9nm using a UV/vis spectrophotometer (Shimadzu, Model 1900 India). The amount of MP in the samples was determined based on the calibration curve generated at a wavelength of 287.9nm. The regression equation for the calibration curve is

y= 643.54 x + 0.013, r² = 0.9563

The dissolution profiles of the different brands of MP tablets were generated from the graph of the amount of MP released versus time. The T70 (average time for 70% of the active drug to be released) was determined.

Chemical Content Determination:

Methylprednisolone pure powder was weighed in amounts of 0.1, 0.2, 0.3, 0.4, and 0.5mg. Each was dissolved separately in 100mL of Distilled water and shaken for 3 min, then further diluted to 200mL with Distilled water and allowed to stand for 15 min. A 2-mL aliquot of the final volume for each weight was taken and further diluted to 200mL with water. The absorbances of the resulting solutions were determined at 289nm, and the calculated value of A (1%) was 289 at 287.9nm.

The method described was used to limit the available brands of MP to the four products comparable in quality to the Branded product. As manufacturers’ interest in MP manufacture and marketing increases, more brands are likely to introduced into the market, and this method can be used to assess the quality and drug-release pattern in the gastrointestinal tract. The objective of this work was to examine the dissolution rate and obtain the PAE to summarily identify the products of MP that can be used interchangeably with respect to the amount of chemical content released in vivo prior to the determination of bioequivalence.

Statistical Analysis:

Statistically significant differences among the brands were analyzed using the F-test with P < 0.2 considered significant.

RESULTS AND DISCUSSION:

Dissolution of drug from oral solid dosage forms is a necessary criteria + for drug bioavailability (i.e., the drug must be solubilized in the aqueous environment of the gastrointestinal tract to be absorbed). For this reason, dissolution testing of solid oral drug products has emerged as one of the most important control tests for assuring product uniformity and batch-to-batch equivalence^11,12. The uniformity-of-weight determination for the eleven brands of MP tablets gave values that comply with the IP specification for uncoted tablets with a deviation less than 5% from the mean value (i.e., maximum deviation value 0.045) (Table 2). The strict adherence to good manufacturing practice (GMP) during the granulation and compression stages ensures tablet uniformity of weight. This is the point in which large intrabatch variations in tablet weight occur. A variation beyond the pharmacopoeial limits indicates unacceptable products. All the brands also passed the friability test; none had weight loss of up to 1% (w/w), with the maximum value being 0.095 (Table 2). Drug products chip at the edges during transportation as a result of abrasion; this is evidence of poor production. All the brands, however, had good compression characteristics exceptsamples 11 and 10, these brands did not meet the requirements for crushing strength.

Table.1 Methylprednisolone Tablet 16 mg. used in study

S. No.	Brand Name	Manufacturer	Pack	Price per Tab. (₹)
1	Predmet 16 Tablet	Sun Pharmaceutical Industries Ltd	10 Tablets	₹9.70
2	Zempred 16 Tablet	Sun Pharmaceutical Industries Ltd	10 Tablets	₹ 9.70
3	Ivepred 16 Tablet	Sun Pharmaceutical Industries Ltd	10 Tablets	₹ 9.70
4	Depotex 16mg Tablet	Zydus Cadila	10 Tablets	₹ 9.72
5	Sterio 16 Tablet	Lupin Ltd	10 Tablets	₹ 9.28
6	Coelone 16mg Tablet	Koye Pharmaceuticals Pvt Ltd	10 Tablets	₹ 9.60
7	Mepresso T 16mg Tablet	Intas Pharmaceuticals Ltd	10 Tablets	₹ 9.74
8	Predace 16 Tablet	Micro Labs Ltd	10 Tablets	₹ 9.78
9	Prelid 16mg Tablet	Glowderma Labs Pvt Ltd	10 Tablets	₹ 9.60
10	MP 16 Tablet	Icon Life Sciences	10 Tablets	₹ 9.60
11	Rednisol 16mg Tablet	Leeford Healthcare Ltd	10 Tablets	₹ 6.62
12	Nupred 16mg Tablet	Nectar Remedies Ltd	10 Tablets	₹ 10.62
13	Mega Pred 16mg Tablet	Venus Remedies Ltd	10 Tablets	₹ 1.10
14	Nolone 16mg Tablet	Keen Healthcare Pvt Ltd	10 Tablets	₹ 9.0
15	Medrol 16 mg. Tablet	Pfizer Itallia Ltd.	16 Tablets	₹12.8

Table 2. Disintegration time, Hardness, weight variation, Friability and Chemical content of Eleven Brands of MP

Brand	Disintegration Time in SGF	Disintegration Time in SIF	Hardness (kg/cm^2)	weight variation N (± RSD)	Friability(%)	Chemical content (%w/w)
1.	11.02.3	11.00.8	4018.9	0.709	16.200.000	97.41.3
2.	10.00.2	10.00.8	4237.3	0.841	16.400.002	96.51.9
3.	11.00.6	11.00.6	4308.6	0.758	16.600.002	98.60.8
4.	11 .00.3	11.00.4	4232.3	0.895	16.650.004	97.50.7
5.	10.00.3	10.00.7	4456.7	0.654	16.250.003	94.40.8
6.	12.00.3	12.00.7	396.58.4	0.995	16.240.002	94.30.5
7.	10.00.7	10.02.6	386.07.6	0.765	16.340.008	90.40.7
8.	11.02.5	11.00.3	4275.6	0.845	16.650.003	98.50.8
9.	11.00.4	12.00.3	3788.8	0.675	16.950.005	92.21.3
10.	11.01.5	13.00.8	447.08.7	0.785	16.460.006	94.30.8
11.	10.00.6	16.00.4	407.80.7	0.975	16.300.002	92.60.8
12.	12.00.3	12.00.7	396.58.4	0.997	16.100.002	94.30.5
13.	11.01.5	11.00.3	4275.6	0.845	16.650.003	98.50.8
14.	11.00.2	10.00.7	4456.7	0.654	16.150.003	95.40.8
15.	11.00.2	11.00.7	394.57.4	0.995	16.140.003	94.30.5

Table 3. Dissolution profile for Fifteen Brands of Methylprednisolone Tablets

	Dissolution		Dissolution
	Parameter in SGF		Parameter in SGF
SAMPLE	T70(min)	C45(%)	T70(min)	C45(%)
1.	32	75	38	75
2.	58	61	57	56
3.	56	59	33	77
4.	65	39	52	67
5.	56	57	37	76
6.	54	39	47	68
7.	54	66	57	63
8.	65	55	51	68
9.	49	61	58	67
10.	55	59	66	65
11.	64	69	57	64
12.	66	69	53	68
13.	59	61	56	64
14.	53	49	50	52
15.	52	50	64	69

Table 4. Content of Methylprednisolone in pure powder form the Branded Brand Using UV Spectroscopy

Weight of sample(g) Tablet (%)	Chemical content of pure Methylprednisolone powdered	Chemical content powder or  Equivalent of generic)  (%)
0.1	98.79 ± 1.4	96.13 ± 1.4
0.2	99.46 ± 2.1	96.16 ± 2.3
0.3	99.23 ± 1.6	96.91 ± 1.6

The observed disintegration times for all the brands of Methylprednisolone investigated were less than the 15-min limit prescribed by the official compendium (Table 2). All tablets of the different generic brands passed the disintegration test. The various brands could have employed disintegrates to improve the penetration of aqueous liquids. The addition of disintegrates (e.g., starch, methyl cellulose) in the right proportion yields tablet products free of disintegration problems (9).

TABLE 5. AUC and Concentration of drug Released in SGF and SIF

BRAN-D	SGF AUC	SGF AUC40	SGF DE*	SGF PAE	SIF T70(%)	SIF AUC	SIF AUC40	SIF DE*	SIF PAE	SIF T70(%)
1.	8605.6	3520.0	0.42	100	39	6893.3	3209.0	0.48	100	37
2.	6038.0	2293.6	0.34	82.23	59	7171.5	2503.6	0.38	75.23	57
3.	7489.5	3527.6	0.41	103.1	58	7322.0	2472.0	0.35	76.21	33
4.	7704.6	3382.4	0.38	94.37	64	7954.9	2641.4	0.36	72.19	37
5.	8626.0	2652.2	0.35	87.19	-	6688.0	1356.0	0.33	73.20	50
6.	7453.7	3165.3	0.36	92.00	57	8636.9	1467.3	0.34	57.96	35
7.	7602.4	2825.8	0.37	94.00	-	5756.9	2456.4	0.27	67.20	46
8.	7708.2	2528.0	0.34	86.60	51	6999.6	1331.3	0.31	66.45	56
9.	7415.0	3215.5	0.32	85.30	50	4870.9	2345.9	0.33	68.76	48
10.	8013.3	3129.0	0.44	97.50	54	6788.7	1031.8	0.38	54.36	38
11.	5018.4	2367.0	0.45	87.60	52	4569.7	2267.8	0.25	65.80	54
12.	6410.21	3750.0	0.42	95.50	53	6654.2	3656.2	0.26	67.8	56
13.	7054.20	3681.2	0.43	92.40	57	6921.2	3540.6	0.27	69.2	51
14.	6879.45	3151.2	0.50	96.20	51	6530.4	3810.0	0.28	68.3	53
15.	5410.30	3245.6	0.34	91.42	56	5410.3	3710.5	0.22	67.2	55

Table 6 : Chemical and Physical Properties (Computed Properties)

Property Name	Property Value
Molecular Weight	374.5 g/mol
XLogP3	1.9
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	2
Exact Mass	374.209324 g/mol
Monoisotopic Mass	374.209324 g/mol
Topological Polar Surface Area	94.8 A^2
Heavy Atom Count	27
Formal Charge	0
Complexity	754
Isotope Atom Count	0
Defined Atom Stereocenter Count	8
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently-Bonded Unit Count	1
Compound Is Canonicalized	Yes

The relative solubility characteristics of MP at room temperature as defined by IP nomenclature indicate that MP is soluble in aqueous solutions at a pH between 2 and 5. It is sparingly to slightly soluble in aqueous solutions at a pH of 7 and freely soluble in aqueous solutions at a pH > 9. This solubility profile allows the use of pH 1.15 (SGF) and pH 7.23 (SIF) as dissolution media for the in vitro testing of MP 625-mg tablets. There was a wide variation in the dissolution of the various brands of MP15 mg tablets in pH 1.15 (SGF), whereas dissolution was comparable in pH 7.23 (SIF). In both cases (SGF and SIF), however, the release after 30 min was lower than the acceptance criterion in the IP and the requirement for an immediate-release dosage form. This is an indication that all the brands fell short of pharmacopoeial standards in this regard. The dissolution rate profile showed that only brand A attained >70% dissolution in 45 min in SGF (PH 1.15) and in SIF (PH 7.23). However, the dissolution profiles of the drug in the simulated fluids gave clear distinction among products (Table 3). Two brands (i.e., 9and 11) did not achieve 70% dissolution in 30 min in simulated gastric fluid and simulated intestinal fluid, which presumes that these brands have different absorption rates. Brands 1, 3, 4, 6, and 7, however, had ≥70% release in SIF, therefore a greater amount of drug absorption is expected to occur in the intestine^13,14. The predicted availability equivalence of brand 8 in SIF and SGF was 66.45% and 86.60%, respectively, and that of 11 product was 68.76% and 85.30%, which clearly indicates that these products are not of comparable quality with the others. The dissolution efficiency (DE) and the predicted availability equivalence were calculated using the equations below¹⁵

DEX = AUCt X / AUCT X (1)

where DEX is the dissolution efficiency of brand X, AUCt X is the area under the dissolution time curve for brand X at time t, And AUCT X is the total area under dissolution time curve for brand X.

DEP = AUCt P / AUCT P (2)

where DEP is the dissolution efficiency of the Branded product, AUCt P is the area under the dissolution time curve of Branded product at time t, and AUCT P is the total area under the dissolution time curve of Branded product.

PAE =DEX/DEP = (AUCT X/AUCTP) *100

The implication of the PAE is to express the relative ease of release and predictive release pattern of the drugs in vivo. Products 2, 3, and 4 with PAE values in SGF and SIF of 82.23%, 103.1%, 94.37% and 75.23%, 76.21%, 72.19%, respectively, are evidently interchangeable with the Branded product 1. However, the dissolution profiles of the drug in the simulated fluids gave a clear distinction among the products. Brands 5, 7, and 9 had ≤70% dissolution in one hour in simulated gastric fluid, which presumes that these brands have a different absorption rate. Brands 2, 3, 4, 5, 6, 7, and 8 had ≤65% release in SGF. The effect of acidic dissolution media on the disintegration and dissolution of the drug is reflected in the poor dissolution profile.

brand 1-9 satisfactorily met the dissolution requirement for coated tablets. Sample 8 also barely achieved 70% dissolution in SIF. The UV spectrophotometric determination of MP content in the eleven brands gave values of 90.27–98.65% (w/w) (Table 4). The PAE calculated for the elev brands of Methylprednisolone were in the range of 54.3–100% in SGF and 86.20–102.1% in SIF (Table 5). The various brands were chemically equivalent because all had chemical content not less than 90% and not more than 100% (w/w)⁸.

SUMMARY:

The presented quality control method is useful in monitoring the production consistency of batch-to-batch product release of each brand of Methylprednisoloneand in comparing the quality characteristics of different brands marketed. The therapeutic equivalence of the drugs must also be investigated by challenging susceptible microorganisms.

ACKNOWLEDGMENT:

The authors are grateful to NRI Institute of Pharmaceutical sciences Bhopal India to provide Instruments facilities for this project.

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Received on 01.11.2019 Modified on 31.12.2019

Accepted on 20.01.2020      ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2020; 10(1):01-06.

DOI: 10.5958/2231-5713.2020.00001.X