Formulation Development and Oral Permeability of Metformin HCl under the Influence of Permeability Enhancers

 

Anil Kumar Adimulapu1*, Naidu Srinivasa Rao2, A. Anusha2, S. Banusha2, V. Akhila2

1School of Pharmacy, Department of Pharmaceutics, The Assam Kaziranga University,

Koraikhowa, NH-37, Jorhat 785006, Assam, India.

2Department of Pharmaceutics, Vikas College of Pharmacy, JNTUK Kakinada,

Vissannapeta - 521215, Vijayawada, Andhra Pradesh, India.

*Corresponding Author E-mail: anilkumar.adi@gmail.com, naidus.rao1@gmail.com

 

ABSTRACT:

Oral drug development is the largest and oldest segment of total drug delivery in the market. It is the fastest-growing and most preferred route of administration. The major challenge in oral drug delivery is the development of novel dosage forms to promote the absorption of poorly permeable drugs across the intestinal epithelium. Metformin HCl is an orally administered biguanide that is widely used in the management of type II diabetes throughout the world. It is a BCS class III drug; it cannot be absorbed orally owing to its very low permeation through the GIT epithelium. The object of the present investigation was to evaluate an oral drug approach that involves co-administration of absorption enhancers. The result indicates that there is a significant impact of permeation enhancers on the improvement in the permeability of the drug. Permeation enhancers and drugs were formulated in tablet form and further evaluated for permeability by using biological membranes. Release of the drug from the tablet in both acidic and alkaline media was found to be higher in the alkaline medium than in the acidic medium. Hence, the addition of absorption enhancers in a formulation at low concentrations can significantly improve the intestinal permeability of Metformin HCl without any side effects like lactic acidosis or gastric irritation and improve bioavailability.

 

KEYWORDS: Metformin HCl, Permeability enhancers, Sustained release, BCS III & IV drugs.

 

 

INTRODUCTION: 

The largest and most established form of medication delivery currently available is oral. It is the most popular and fastest-growing method of administration. The creation of innovative drug products to support the bioavailability of weakly permeable medicines across the intestinal epithelium is the main problem in oral medication administration. Biguanides, such as Metformin HCl, are often used orally to treat type 11 diabetes all over the world. It is a BCS class III medication that has very little penetration into the GIT epithelium and cannot be taken orally.

 

The contemporary study aspired to assess an oral medication delivery strategy that includes the co-administration of absorption boosters. The outcome shows that permeation enhancers have a considerable positive impact on the improvement.1

 

A significant portion of currently marketed medications are classified as class III biopharmaceuticals. Drugs with low intrinsic membrane permeability are unable to be administered orally due to their poor permeability across the GIT epithelium, which is likely caused by their low solubility, low hydrophobicity, and zwitter ionic character at physiological pH and high molecular weight. The Biguanides medication class includes the oral anti-diabetic medicine Metformin HCl, which is the first line of management for type 2 diabetes.2 The most widely used medication worldwide is Metformin. The creation of a Metformin dosage form to improve absorption of weakly permeable drugs across the gastric epithelium faced the following key problems in oral medication administration.3 As a result of its shorter, variable biological half-life of 1.5 to 4.5hours, the maximum suggested daily dose of Metformin HCl is 2.5 g given in three doses with meals. This dose must be repeated to sustain the effect on plasma concentration. Because of its high dose and despite its positive clinical response, Metformin HCl suffers from several issues, such as lactic acidosis and stomach irritations, when used as a chronic therapy. Bioavailability is sub-60%, which is poor. Metformin HCl requires prolonged drug release because it is frequently used, yet one of the main restrictions is the high dose. Serious gastrointestinal irritations result from high solubility4 As a result, the following investigational information and study data are required to build one of the unique Metformin HCl ways for better therapeutic.5

 

Hence To develop a novel Metformin HCl strategy for superior therapeutic impact, the following investigational information and study data are required.

 

MATERIALS AND METHODS:

Materials:

Metformin HCl (Aurobindo Pharma Pvt. Ltd., Hyderabad), fatty acids, and chitosan (Signet Mumbai, Chemika Biochemika Reagents), All other components of the standard analytical class are used.

 

Methods:

STEP 1: Determination of Partition Coefficient:

Chitosan, fatty acids (myristic acid, oleic acid, and lauric acid) in different molar ratios, and chloroform partition The coefficients of Metformin HCl with or without permeation enhancers were determined. There was saturation between these two stages. In the aqueous phase, the chemicals were dissolved.6 At room temperature, the buffer and chloroform solutions were shaken for an hour. After the samples were divided into two phases, the drug content was examined using UV spectrometry at a maximum wavelength of 234 nm. The following equation was used to determine the partitioning coefficient: Where ac and ab are the drug's concentrations in buffer and chloroform, respectively.The p/w for Metformin HCl alone is only (0.037. The PC/buffer value of Metformin HCl, a hydrophilic medication with many polar groups, was incredibly low (0.037). However, the Po/buffer pH 6.8 values improve when absorption enhancers are combined with them. Different ratios of permiabilty enhancers shown in Table no1.

 

STEP 2: In-vitro Permeability Studies by Using Everted Sac Intestine Method:

Everted Sac Modification Method:

The small intestine of a malnourished goat that was killed under CO2 anaesthesia was swiftly removed to prepare everted intestinal sacs. The jejunum was removed, repeatedly rinsed with room-temperature saline solution, and then immediately submerged in an oxygenated buffer solution at 37°C. The intestine was then carefully everted over a steel rod, stuffed with brand-new oxygenated buffer solution, and separated into around 4.5 cm-long sacs with silk sutures. Sacs were put in 25 mL oxygenated buffer solutions containing 25 g/mL Metformin at 37°C with or without permeability enhancers at various doses after pre-incubating for 5 min in oxygenated buffer solutions at that temperature. Sacs were taken out and dried out at predetermined time intervals. The serosal fluid was removed when the sacs were cut open.7

 

Table 1: Determination of partition coefficient by using fatty acids

Batch code

Dose (mg)

Permeation enhancer

Different Concentration (%)

Partition coefficient

 

 

P- 1(L)

 

 

400mg

 

 

Lauric acid

P- 1.1 (L)

10

0.280

P-1.2 (L)

20

0.421

P-1.3 (L)

30

0.629

P-1.4 (L)

40

0.912

P-1.5 (L)

50

1.106

 

 

P- 2( M)

 

 

400mg

 

 

Myristic acid

P-2.1 (M)

10

0.152

P-2.2 (M)

20

0.354

P-2.3 (M)

30

0.494

P-2.4 (M)

40

0.873

P-2.5 (M)

50

1.012

 

P- 3(0)

 

400mg

 

Oleic acid

P- 3.1 (O)

10

0.254

P- 3.2 (O)

20

0.616

P- 3.3  (O)

30

0.986

P- 3.4  (O)

40

1.133

 

Table 2: Determination of partition coefficient by using chitosan:

Batch code

Dose (mg)

Permeation enhancer

Different Concentration (mg)

Partition coefficient

P- 4(C)

 

400

 

Chitosan

P- 4.1(C)

100

0.883

P- 4.2(C)

200

1.424

 

Step 3: Composition of Tablet Formulation:

Weigh precisely. Chitosan, HPMC K15, and Eudragit L 100 were sorted through #40 mesh along with Metformin HCl. Additionally, other excipients, including PVP and lactose, were incorporated in the appropriate amounts. Materials were combined, ground, and granulated with water and isopropyl alcohol (1:1) using a mortar and pestle. They created an A #10 mesh that was used to filter the wet bulk before it was dried for 45 minutes at 50°C. Granules of dried material were run through #18 mesh. Talc and magnesium stearate were precisely weighed and sieved through #40 mesh. And lubricants were combined with the aforementioned components for two minutes. Tablets containing the necessary amount of blend were compacted. The tablets were made with a rotary tablet compression machine with a 9-mm die (Cadmach, Press, India). Every formulation had 400 mg of Metformin HCl.the composition of formulation shown in Table no 2.


 

Table 3: Composition of Metformin HCl tablets with permeation enhancers (PE) by Wet granulation method.

Bath code

Metformin HCL (mg)

Permeation enhancer (mg)

HPMC K15

EudragitL100

PVP

Lactose

Mg stearate

Talc

F1

400

200

10%

10%

4%

112

2%

2%

F2

400

200

20%

10%

4%

32

2%

2%

F3

400

200

20%

20%

4%

-

2%

2%

Total Tablet Weight (800 mg/tablet)

 

RESULTS AND DISCUSSION:

Determination of Partition coefficient by using fatty acids:

Long-chain fatty acids like oleic acid and medium-chain fatty acids like lauric acid have been demonstrated to increase the permeability of several hydrophilic drugs by dilatation of the tight junction and alteration of the cytoskeleton of the intestinal epithelial cells without significant cytotoxicity. For fatty acids like lauric acid, myristic acid, and oleic acid, different concentrations are 10, 20, 30, 40, and 50%; among these concentrations, 50% concentrations of lauric acid, myristic acid, and 40% of oleic acid were found in ≥ 1 partition coefficient value. Although there is no concrete proof, the following theories on the mechanism of action have been put forth: altered membrane fluidity, membrane destabilisation brought on by the breakdown of cholesterol, and disturbed lipid packing with fatty acids. Permeability also rises when fatty acid concentrations rise. Partition coefficient value for pure drug = 0.037, ≤ 1, as shown in Fig. 1.

 

 

Fig 1: Graphical representation of partition coefficient by using fatty acids

 

Determination of partition coefficient by using Chitosan:

These polymers were able to attach firmly to the epithelium and cause the TJ protein ZO (Zonula occludens) and cytoskeleton F-actin to be redistributed.8 This was followed by improved transport along the paracellular route. The tight junction is also affected by chitosan and its salts, which decrease its integrity and raise intestinal permeability. Chitosan comes in weights of 100 mg and 200 mg, and it was discovered that the 200 mg of permeation enhancers had a partition coefficient value of 1. Chitosan, a positively charged bioadhesive polysaccharide, has been found to significantly reduce liquid clearance from intestinal absorption and improve epithelial absorption of peptides while barely damaging the mucosal membrane of the intestinal mucosa. Figure no 2 displayed the outcomes.9

 

Fig 2: Graphical representation of partition coefficient by using chitosan

 

Step 2: In vitro Everted sac goat intestine for absorption studies:

The different permeation enhancers above were used to determine the permeability by using the everted sac intestine method. In the different thicknesses of intestines in trial 1, the pure drug permeated at 2hr is 3.88mg, and with the permeation enhancers of fatty acids (oleic acid, lauric acid, myristic acid, and chitosan), the drug permeated at 2hr is 4.241, 4.123, 5.281, and 6.369g/mL. Of all these enhancers, oleic acid and chitosan show the maximum drug permeated. In trial 2, using oleic acid and chitosan, they show 5.196 and 6.446mg, respectively, among these permeation enhancers. Chitosan shows the maximum drug permeation. So I selected chitosan for further work. These optimised concentrations of permeation enhancers are used for further formulation. The results were shown in Table 4.

 

Table: 4 Partition coefficient values of Metformin with different permeability enhancer

S. No

Time

Metformin HCl

Fatty acids

Chitosan

P- 1.5 (L)

P- 2.5 (M)

P- 3.4 (O)

P -4.2 (C)

1

30min

1.74

1.581

1.21

2.084

2.988

2

60min

2.73

1.673

2.40

3.402

3.839

3

90min

3.15

3.872

2.91

5.194

4.294

4

120min

3.65

4.241

4.123

5.281

6.369

 

 

Fig 3: Graphical representation of permeability study by using intestine    

Dissolution studies of Metformin HCl with permeation enhancer (Chitosan):

The formulations F1-C, F2-C, and F3-C contain permeation enhancer 200mg with different concentrations of HPMC K15 and Eudragit L 100 formulation prepared by wet granulation method. These formulations were evaluated for drug release studies in different dissolution media, namely pH 1.2 HCl (for 2 hr) and pH 6.8 phosphate buffer.10 The formulation F1-C contains 200mg of chitosan, 10% HPMC K15, and Eudragit L 100, the maximum amount of the drug released at 12hours. The formulation F2-C (20% HPMC K15 and 10% Eudragit L 100) is the maximum amount of drug released at 12hours. The formulation F3-C 20% HPMC K15, Eudragit L 100, releases the maximum amount of the drug at 18 hours. It follows zero-order kinetics and the Peppas mechanism. Formulation (F3-C) is the amount of drug release at 18 h when compared to others, so it is an optimised formulation. The results are shown in Fig. 4.

 

 

Fig 4: Drug release profile of optimized formulation compared with Metformin HCl with Chitosan

 

CONCLUSION:

This study offered a novel, potentially effective remedy for the limited permeability of BCS class III drugs. This method of drug encapsulation is based on the molecular dispersion of the drug with permeability enhancers like chitosan (a natural enhancer). The mixture was made using a permeability enhancer because a matrix may be made using either a melting congealing technique or a kneading technique. Metformin HCl permeability may expect a significant improvement, which would also increase bioavailability. The results of this study may also pave the way for the use of a similar technique to improve medication absorption mechanisms via the paracellular pathway for an immediate and comprehensive pharmacological effect. And it was determined that chitosan was the optimum material for improving the permeability of Metformin HCl.

 

ACKNOWLEDGMENT:

We sincerely express our thanks to the Management of Vikas College of Pharmacy, Vissannapeta, Vijayawada, and Andhra Pradesh for providing all the facilities to carry out this research work.

 

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Received on 23.08.2023            Modified on 08.10.2023

Accepted on 14.11.2023           © RJPT All right reserved

Research J. Pharm. and Tech 2024; 17(7):3209-3212.

DOI: 10.52711/0974-360X.2024.00502