Formulation development and evaluation of Sitagliptin Phosphate Monohydrate sustained release tablet by using natural polymers

Diabetes mellitus, which is sometimes just called diabetes, is a metabolic condition that results in elevated blood sugar levels. Insulin transports blood sugar into your cells so that it can be stored or used as fuel. ^[1]

Types of diabetes

There are a few different types of diabetes:

Type 1: An autoimmune condition is type 1 diabetes. The cells that produce insulin in the pancreas are attacked and destroyed by the immune system. The reason for this strike is unknown.

Type 2: When sugar accumulates in your blood and your body grows resistant to insulin, type 2 diabetes develops. Type 2 diabetes is the most prevalent kind, with 90% to 95% of persons with the disease having this reliable source.

Gestational: High blood sugar during pregnancy is known as gestational diabetes. This kind of diabetes is brought on by the placenta's production of insulin-blocking substances. ^[2]

Type 1 diabetes

What specifically causes type 1 diabetes is unknown to doctors. The pancreatic beta cells that produce insulin are unintentionally attacked and destroyed by the immune system. Some persons may have a genetic component. A virus may also trigger an attack on the immune system. ^[3]

Figure 1: Autoimmune attack in type 1 diabetes

Type 2 diabetes

Genetics and lifestyle factors work together to cause type 2 diabetes. Being obese or overweight also raises your risk. Your cells become more resistant to the effects of insulin on blood sugar when you carry excess weight, particularly in your abdomen. This illness is inherited. Genes that increase the risk of type 2 diabetes and obesity are shared by family members. ^[4]

Figure 2: Type 2 Diabetes

Gestational diabetes

Hormonal changes during pregnancy might lead to gestational diabetes. Hormones produced by the placenta reduce the sensitivity of a pregnant person's cells to the effects of insulin. Insulin resistance, which occurs when muscle and adipose cells are unable to react appropriately to normal insulin levels, is a hallmark of type 2 diabetes, a chronic metabolic illness. The Centers for Disease Control and Prevention predict that there are currently 26 million Americans with type 2 diabetes mellitus (DM), and by 2050, that number is expected to quadruple. One Diabetes is referred to be a "silent killer" because, if left untreated, chronic complications kill people more frequently than hyperglycemic crises.  ^[2,3] One inhibitor of dipeptidyl peptidase-4 (DPP-4) is sitagliptin phosphate. Sitagliptin inhibits the enzyme dipeptidyl peptidase 4 (DPP-4) in a competitive manner. The gastrointestinal hormones GLP-1 and GIP, which are produced in reaction to a meal, are broken down by this enzyme. They can decrease the pancreatic release of glucagon and boost insulin secretion by blocking GLP-1 and GIP inactivation. Blood glucose levels are brought closer to normal as a result. Designing and refining Sitagliptin Phosphate sustained release tablets using the direct compression technique was the aim of this work. Directly compressible lactose was used to compress the optimum formulation into tablets. A dosage of 100 mg of sitagliptin phosphate was administered. Therefore, Sitagliptin Phosphate sustained release tablets were made in order to preserve the medicine's bioavailability and lower the frequency of drug administration. ^[5]

Purpose of the Study

The oral route of administration remains the most popular because of its many benefits, which include patient compliance, simplicity of intake, pain avoidance, and adaptability. The most often used dose forms are capsules and tablets. Taking traditional dosage forms on time and more than once a day causes variations in the drug's plasma concentration, which can cause missed doses. Sustained release formulations have been created to get around this. The benefits of these include less blood level swings, fewer doses, improved patient convenience and adherence, fewer negative side effects, and lower total medical expenses.

AIM:

To formulate and evaluate Sitagliptin Phosphate Monohydrate sustained release tablet by using natural polymers for type 2 diabetes mellitus.

OBJECTIVE

• To procure drug excipients and polymer from different sources.
• To study compatibility of drug and excipients used for the formulation of sustained release tablets.
• To prepare and evaluate sustained release tablets using natural polymers.
• To optimize of prepared formulation on the basis of its dissolution profile.
• To prepare a stable dosage form and perform its stability study.

Drug Profile

Sitagliptin

Chemical structure:

Colour: White

Molecular Formula: C₁₆H₂₀F₆N₅O₆P

Catagory: Antidiabetic

Synonyms: Sitagliptin Phosphate, Januvia

CAS No.: 654671-77-9

Molecular Weight: 523.32 g/mol

Melting Point: 206-208 ⁰C

Bioavailability:  87 %

BCS Classification: class-III (High soluble low permeable)

Dose: 100 mg twice a day with or without food ^[8,9]

MATERIALS & METHOD

Ingredients List

Table 1: Ingredients used for Sitagliptin Phosphate Monohydrate sustained release tablet

Prepration of Sitagliptin Phosphate Monohydrate sustained release tablet

1. Sitagliptin PM, Xanthan gum, Microcrystalline cellulose (MCC), Lactose, Magnesium stearate and Talc were passed through mesh no. 60 separately and collected.
2. Sitagliptin PM, Xanthan gum and Lactose were mixed uniformly with gentle trituration using mortar and pestle to get a uniform mixture.
3. After trituration mixer was placed in a RMG (Rapid Mixer Granulator) for 30 mins at 150 rpm.
4. Finally, magnesium stearate and talc were added and mixing was continued for further 5 min.
5. The mixed blend of drug and excipients were compressed using 10.5 mm punch on 10 stations “B” Tooling Rotatory Tablet Punching Machine to produce convex faced tablets, weighing 350 mg each.

Before tablet preparation, the mixture blend of all the ingredients were subjected to precompression parameters like Angle of repose, Bulk density, Tapped density, Compressibility index and Hausner’s ratio.

EXPERIMENTAL WORK

1. Preformulation study:

A.  Drug Characterization:

 Drug characterization parameters such as colour, odour and appearance were analysed for the procured drug samples

Table 2: Drug characterization parameters

B.  Determination of melting point:

The melting point of Sitagliptin PM was found to be in the range of 206-208 ⁰C which comply with reported melting point of Sitagliptin PM

C.  Solubility study:

The solubility study of Sitagliptin PM was carried out by using different solvent systems as per the literature. The solubility results were shown in table

Table 3: Results for solubility study

UV-visible spectrophotometric analysis

The UV-visible spectrophotometric analysis of drug was carried out 0.1N hydrochloric acid as well as Phosphate buffer 6.8 pH were used as solvent system for determination of λ _max 40 µg/ml of Sitagliptin PM sample was used and λ _max was found as 266 nm for 0.1N HCl and 267 nm for PB 6.8 pH respectively.

Figure 3: 40 PPM solution of Sitagliptin PM in 0.1 N hydrochloric acid

Figure 4: 40 PPM solution of Sitagliptin PM in Phosphate buffer 6.8 pH

Preparation of Calibration curve for Sitagliptin PM in 0.1 N Hydrochloric acid

The calibration curve of Sitagliptin PM was drawn by measuring the absorbance of different concentrations in 0.1N hydrochloric acid at 266 nm

Table 4: Calibration curve for Sitagliptin PM in 0.1N Hydrochloric acid

Figure 5: Calibration curve for Sitagliptin PM in 0.1N Hydrochloric acid

The calibration curves were linear and obeyed Beer-Lambert’s law in the concentration range 10-50 μg/ml. The correlation coefficient values were 0.9964 indicating excellent linearity of the data.

B. Preparation of Calibration curve for Sitagliptin PM in Phosphate buffer 6.8 pH:

The calibration curve of Sitagliptin PM was drawn by measuring the absorbance of different concentrations in phosphate buffer 6.8 pH at 267 nm.

Table 5: Calibration curve for Sitagliptin in Phosphate buffer 6.8 pH

Figure 6: Calibration curve for Sitagliptin PM in phosphate buffer 6.8

Drug excipient compatibility study:

Drug excipient interaction studies are significant for the successful formulation of every dosage form. Fourier Transform Infrared (FTIR) Spectroscopy studies were used for the assessment of physicochemical compatibility and interactions, which helps in the prediction of interaction between drug and other excipients. In the current study 1:1 ratio was used for preparation of physical mixtures used for analyzing of compatibility studies.

Table 6: Drug excipient compatibility

Note- NCC means No Conformational Change

Formulation development of Sustained Release Tablets

All the formulations were prepared by Direct Compression method. The compositions of different formulations are given in Table.

Table 7: Formulation strategy

Evaluation of formulated batches:

A. Precompression parameters

The powder blend from all the batches were evaluated for density and flow property parameters which includes Bulk density, Tapped density, Compressibility index, Hausner’s ratio and Angle of repose.

Table 8: Precompression parameters

B. Post compression parameters:

1. Physical appearance:

The tablets from all trial batches were white round convex shaped beveled edge with having plane upper and lower side.

2. Thickness and diameter:

The thickness and diameter for all the tablets were measured by using Vernier caliper by picking the tablets randomly. Thickness was found in the range from 5.0 mm to 5.2 mm respectively and diameter was found in the range of 9.7 – 9.9 mm. Uniformity in the values indicates that formulations were compressed without sticking to the dies and punches.

3. Hardness:

Monsanto hardness tester was used for the determination of hardness for all the batches Hardness was found to be in range of 7.5 kg/cm² to 9 kg/cm². The hardness for all formulated batches were uniform and possess good mechanical strength with sufficient hardness

4. Friability

Tablets from all batches were evaluated by using Roche Friabilator and Friability was acceptable range 0.29 to 0.86 (Less than 1%). The result was given in table

Table 9: Post compression parameters

5.Drug content

Drug content uniformity test was performed for all formulated batches and results were expressed in table 10. The drug content was found to be between 98- 102 % which was under specified limit.

Table 10: Drug content

7. In vitro dissolution test:

The in vitro evaluation of all the formulated batches were carried out for 10 hrs. by using 0.1N hydrochloric acid (0 – 2 hrs.) and Phosphate buffer 6.8 pH (3 – 10 hrs.)

Table 11: In vitro dissolution

Figure 7: In vitro dissolution study

Evaluation of optimized batch:

Table 12: Evaluation of optimized batch

Stability study

The optimized formulation batch of Sitagliptin Phosphate Monohydrate sustained release tablet was wrapped in an aluminum foil and subjected to 40 ± 2⁰C temperature and 75 ± 5% RH in stability chamber for the period of 1 months. The formulation was analyzed for Physical appearance, Thickness, Hardness, Drug content and Dissolution study. In any rational design of dosage forms for drug, the stability of the active component is the major criteria in determining their acceptance or rejection. Stability studies were carried out as per ICH Q1A(R2) guidelines.

Table 13: Stability study