Formulation and Evaluation of Capsule-in-Capsule Technology for Biphasic delivery of Glipizide

Rupali Rathod, Manoj Bari, Shaikh Samir

Shri Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner, Dist. Jalgaon.

*Corresponding Author E-mail: rupalirathod3447@gmail.com

ABSTRACT

In the present research work, to formulation and evaluation of capsule-in-capsule technology for biphasic delivery of Glipizide. The advantages of fast releasing liquid-filled-capsules and slow release beads-filled-capsules were combined to meet the optimized requirements of our biphasic drug delivery system. Glipizide slow releasing beads were prepared by ionotrophic gelation method by using natural polymers like Sodium alginate, Pectin and were filled into a smaller capsule. Glipizide fast releasing liquid dispersion was prepared by using either Castor oil carriers and further prepared a glipizide emulsion. This fast releasing liquid and slow releasing beads-filled-capsule was further inserted into a bigger capsule body and Seal the capsule by hydro alcoholic solution. The various formulation batches were subjected to physicochemical studies, entrapment efficiency, drug content, in vitro drug release and stability studies. Interaction studies reveal that there was no interaction between drug and polymers employed in this study. The optimized capsule-in-a-capsule formulation released 22.65±0.74% of drug at the end of 30 min and 95.04±0.88% of drug at the end of 12h. The drug release profile of Glipizide capsule-in-a-capsule formulation fits well with Pepas model followed by zero order, first order and Korsemeyer-peppa’s model. Korsmeyer-Peppas model analysis indicated that the drug release followed non-Fickian transport mechanism. The stability results indicate that the various parameters of our optimized formulation are not affected on storage at 45°C/75%RH up to 4 months. Target of capsule-in-capsule drug delivery loading dose reaches therapeutic drug level in blood plasma for quicker onset of action and Maintenance dose which maintain an effective therapeutic level for prolong period. The prepared Glipizide biphasic cap-in-cap will be used for treatment of Diabetes.

KEYWORDS: Biphasic drug delivery system, Capsule-in-a-capsule formulation, Fast releasing liquid-filled-capsules, slow release beads-filled-capsules.

1. INTRODUCTION:

One of the most popular solid dosage shapes used for oral administration of active substances is the capsule. Capsule-in-capsule technology is an innovative approach
to drug delivery that involves placing one or more smaller capsule inside a larger one.

Solid dosage forms can be divided into two main categories¹ immediate release dosage forms, where disintegration and subsequent drug release and dissolution occurs in stomach, and the (non-immediate) modified-release technologies, which utilize polymers to alter the site or time of drug release within gastrointestinal tract.² This technology has the potential to improve multiple drugs or combination of drug at specific location in the body.¹⁷The Biphasic drug delivery system are designed to release a drug at two different rates In Diabetes will found to be more beneficial when it delivered in a biphasic manner Glipizide belong to class Sulfonylurea it help to stimulate the released of insulin from the pancreas directing in body to store blood sugar Immediate release dose fraction reaches therapeutic drug level in blood plasma quickly after administration while extended release provide dose fraction to maintained therapeutic level.^6,18 A broad range of therapeutic applications can be achieved by using single oral capsule dosage units comprising capsule in-a-capsule technology.^5,8

2. MATERIALS AND METHOD:

Glipizide obtained from medley Pharma Ltd., Sodium alginate, pectin, Castor oil, Calcium chloride Empty hard gelatin capsules (size 00 and size 4) were obtained as a gift sample from Sunil health limited, New Delhi, Delhi. All other materials used were of analytical grade.

2.1 Formulation of Glipizide Capsule-in-Capsule Technology: To prepare a novel Glipizide capsule-in-capsule technology the prepared optimized sustained release beads equivalent to 5 mg of Glipizide were filled in size 4 hard gelatine capsule.³ The Immediate release Glipizide emulsion equivalent to 5 mg of Glipizide were filled in size 00 hard gelatin capsule. This prepared sustained release smaller capsule was filled into bigger capsule body size 00 using medicine droppers. The filled capsules were stored at room temperature until testing.^{7, 9}

2.1.1 Preparation of Glipizide emulsion (immediate releasing phase): Weighed the entire ingredient properly. Take 50mg of Glipizide drug Dissolve in required quantity of castor oil. Then added appropriate amount of surfactant (span 80) in the solution. The above preparation gently stirred with a mechanical stirrer.₍₅₎ All component mixed properly.¹²The co-surfactant (polyethylene glycol) added drop wise to this preparation until the solution clear. The solutions were then stirred for 15 min to allow equilibrium.^{15, 19}

2.1.2 Preparation of Glipizide Beads (Sustained Release Phase): Weigh the entire ingredient properly. Weights 2g of Sodium alginate add into 100ml of water and stirred on magnetic stirrer or 15 min required quantity of Glipizide (625mg) was dispersed in 2ml of N-N-dimethyl formamide these solutions added slowly in alginate solution under stirring. In another conical flask take 100 ml of water add 5g calcium chloride.¹³ The alginate solutions poured in burette then add drop wise in calcium chloride solution with continuous stirring on magnetic stirrer. The formed beads were allowed to stand for 5 min in solution (for hardening). Then filtrate the beads and wash with distilled water. Drying overnight at room temperature (air dry) next day dry the beads in oven 50⁰C to 60⁰C temperature.^{2, 5}

Each batch contains 625 mg of Glipizide. Drug equivalent to 5 mg is taken for single sustained release dose.

Tablet No. 1: Composition of Optimized Batches by Central Composite Design

For Sustain Release Phase

Ingredient	Batches
Ingredient	BFC1	BFC2	BFC3	BFC4	BFC5	BFC6	BFC7	BFC8	BFC9
Glipizide	0.625	0.625	0.625	0.625	0.625	0.625	0.625	0.625	0.625
Sodium Alginate	3	3.414	2	2	1	2	0.585	3	1
Calcium chloride	2	3.5	5.621	3.5	2	1.37	3.5	5	5

For Immediate Release Phase:

Table No: 2 Immediate release Phase

Ingredient	Batches
Ingredient	LFC1	LFC2	LFC3	LFC4	LFC5	LFC6	LFC7	LFC8	LFC9
Glipizide	0.050	0.050	0.050	0.050	0.050	0.050	0.050	0.050	0.050
Castor oil	9	9	5.5	5.5	10	5	2	2	0.5
Span 80	3	15	9	0.5	9	17	15	3	9
Tween 80	20	20	20	20	20	20	20	20	20
Polyethylene glycol	10	10	10	10	10	10	10	10	10

3. EVALUATION PARAMETER:

3.1 Bulk Density: Accurately weigh the beads, which are transferred in 100ml graduated cylinder. Carefully level the beads without tapping, and read the unsettled apparent volume. Calculate the apparent bulk density in gm/ml by using the following formula.^1,4

Bulk density= (Mass of powder in gm )/(Bulk volume of powder in ml)

3.2 Tapped Density: Accurately weigh required quantity of beads, which is transferred in 100ml graduated cylinder. Initial volume is observed. The cylinder will be tapped initially 500 times and note the tapped volume to the nearest graduated units.¹³ The tapping can be repeated additional 750 times. Again the tap volume is measured to the nearest graduated unit. Tapping can also be repeated again 1250 times. Calculate the tapped bulk density in gm/ml by the following formula.^21,22_.

Tapped Density=(Weight of powder in gm )/(Tapped volume of powder in ml)

3.3 Angle of Repose: Angle of repose method was employed to assess the flow ability of the beads. Beads were allowed to fall freely through the funnel fixed at 2cm above the horizontal flat surface until the apex of conical pile just touched the tip of the funnel. The angle of repose (θ) was determined by the formula, where, ‘h’ is the cone height of beads, ‘r’ is the radius of circular base formed by the beads on the ground.^11,24

Ɵ=tan-1(h/r)

3.4 Determination of UV Spectrum: Glipizide Solution (10μg/ml) was prepared in phosphate buffer pH 6.8 and pH 1.2HCl This solution was scanned under a double-beam UV visible Spectrophotometer (Shimadzu-1800) and the spectrum was recorded in the wavelength ranges between 200-400nm.

3.5 Fourier Transform Infrared Spectroscopy (FTIR): The FTIR studies were carried out using FTIR 1-S Affinity used to identify any drug and excipients interaction. The infrared spectra of Glipizide and a mixture of drugs and excipients that examined using FTIR¹⁴_,

3.6 Differential Scanning Calorimetry (DSC): DSC analysis was used to measure melting temperature and also to check the possibility of any interaction between drug and excipients used in the formulation²⁴_.

3.7 Entrapment Efficiency: Accurately weighed quantities of beads equivalent to 5mg of Glipizide were placed in 100mL of 0.1N HCl and Phosphate buffer pH 6.8. then filter the solution pull out 1ml solution and make up to 10 ml The solution was centrifuged using the centrifuge at 4200 rpm for 30min; the supernatant layer of the liquid was assayed by UV-spectroscopy at 274nm. The encapsulation efficiency was determined by the following equation.⁴

3.8 Drug content uniformity: Liquid dispersion and beads equivalent to 10mg of Glipizide respectively was extracted in phosphate buffer of pH 6.8 and pH 1.2 HCl (0.1N HCL). The solution was filtered through a Millipore filter (0.45μm pore size) and the drug content was determined spectrophotometrically at λ max of 274nm after suitable dilution. The studies were carried out in triplicate and the mean values were noted indicating the reproducibility of the results.^22,23

Drug Content (%) =(Test Absorbance)/(Standard Absorbance)×100

3.9 Evaluation of Capsule-in-Capsule formulation of Glipizide

In Vitro Dissolution Studies:

A. Immediate Released Liquid Dispersion of Glipizide: The dissolution studies were carried out using USP dissolution test apparatus Type-II (E Dissolution studies were carried out using USP XXIII dissolution test apparatus II basket type (Electrolab TDL08L) at a rotation speed of 100rpm and at 37±0.5°C using 900mL of 0.1N HCl (pH 1.2) for two hours.^1,2,4 A 5mL sample was withdrawn at 30min time intervals and replaced by an equal volume of pre-warmed 0.1N HCl (pH 1.2). Samples withdrawn were filtered through whatmann filter paper (0.45µm). The amount of lornoxicam released was analysed at 374nm using a Shimadzu UV-spectrophotometer. The studies were carried out in triplicate and the mean values plotted verses time with standard error of mean, indicating the reproducibility of the results.^19,20_.

B. Sustained Release Beads and Capsule-in-Capsule Formulation: Dissolution studies were carried out using USP dissolution test apparatus II Paddle type (Electrolab TDL08L) at a rotation speed of 100rpm and at 37±0.5°C using 900ml of 0.1N HCl (pH 1.2) for two hours and remaining hours in pH 6.8 phosphate buffer. A 5 ml sample was withdrawn at 30min time intervals and replaced by an equal volume of pre-warmed 0.1N HCl (pH 1.2) and phosphate buffer pH 6.8, respectively¹⁶. Samples withdrawn were filtered through whatmann filter paper.

The amount of Glipizide released was analysed at 274nm for samples tested in 0.1N HCl and the phosphate buffer pH 6.8 using a Shimadzu UV-spectrophotometer.^{10,7, 15}

3.10 Release kinetics studies: To study the release kinetics in vitro release data was applied to kinetic models such as zero-order, first order, Higuchi and Korsemeyer-Peppas⁷

4. RESULT AND DISCUSSION:

Glipizide capsule-in-a-capsule technology designed in this study consists of two phases; immediate and sustained releasing phase. The immediate dose (i.e. loading dose) will be useful for quicker onset of action to relieve from Diabetes and the sustained dose (i.e. maintenance dose) were helpful to reduce the frequency of doses, throughout the day. The device was formulated into two steps: First Glipizide was prepared as sustained release beads with natural polymer and filled into a size 4 leakage proof capsule which was further filled into a size 00 leakage proof capsule body; second Glipizide was prepared as a liquid dispersion with solubilising solvent and filled into the bigger capsule body containing smaller capsule filled beads.

4.1 Fourier Transform Infrared Spectroscopy (FTIR):

The IR spectra of Glipizide with Sodium alginate and Pectin did not reveals any extra peaks which confirms the absence of chemical interactions between Glipizide and excipients

4.2 Differential Scanning Calorimetry (DSC) DSC thermograph indicated that the melting point of the pure drug Glipizide was 205.28 °C and the drug-excipient mixture was 205.20°C. There was no difference between both melting point indicated that no chemical and physical interaction.

Fig. No 2: DSC Thermogram of Glipizide Fig. No. 3: DSC Thermograms of Excipient

4.3 Results of angle of repose, drug content and drug entrapment

Table No: 3 Evaluation of Beads

Batches	Angle of Repose Ѳ	Drug Content (%)	Drug Entrapment Efficacy (%)
BFC1	18.72	96.20	81.75
BFC2	25.16	95.45	79.68
BFC3	28.58	92.53	82.12
BFC4	28.30	95.42	93.13
BFC5	23.17	97.28	89.34
BFC6	25.68	90.87	85.62
BFC7	30.72	98.32	90.41
BFC8	26.61	97.64	78.30
BFC9	27.64	94.87	76.06

The angle of repose values ranged from 18.72⁰ to 30.72⁰ which indicate good flow properties of the beads. The mean drug content of liquid dispersion and beads was studied and the values were found to be more than 93%. The drug entrapment efficiency of the sustained release beads was also studied and the values were found to range between 76.06% to 93.13% and the maximum drug entrapment was found to be in BFC-4 batch i.e. 93.13% as shown in Table. No.4.3

4.4 Evaluation of optimized Batch of Glipizide emulsion:

Table No: 4 Drug Content

Sr. No.	Batches	Drug Content (%)
1	LFC 1	98.67
2	LFC 2	94.32
3	LFC 3	95.86
4	LFC 4	97.30
5	LFC 5	97.13
6	LFC 6	98.53
7	LFC 7	96.48
8	LFC 8	97.94
9	LFC 9	96.73

The mean drug content of liquid dispersion was studied and the values were found to be in range 94.32% to 98.67

4.6 In vitro Dissolution Study:

4.6.1 In-Vitro Dissolution Studies of Batches of Capsule-in-Capsule Technology

The Result were evaluated for 2 Hrs. Among of the 9 batches LFC 3 showed uniformity of the drug release up to 2 hrs. And was considered as ideal formulation of immediate release phase. The evaluation result of in vitro drug release was mentioned in fig no 4 The result were evaluated for 12 Hrs. among of the 9 batches BFC 4 showed uniformity of the drug release up to 12 hrs. and was considered as ideal formulation of sustained release beads. The evaluation result of in-vitro drug release are mentioned in fig. 5

4.7 Release kinetics studies:

The drug release from capsule-in-a-capsule formulation fits well with Korsemeyer Peppas model which is generally used to analyse the release mechanism when more than one type of release phenomenon is operational. Good linearity was observed with high ‘R2’ value – 0.9793. The value of release exponent ‘n’ is an indicative of release mechanism. The value of ‘n’ obtained for the optimized formulation was found to be 1.158 suggesting probable release by non-Fickian.

Fig. No. 4: In – Vitro Drug Release of LFC 1 to LFC 9

Fig. No. 5: BFC1 to BFC 9 Batch for S Batch for Immediate Release Phase Sustained Release Phase

Table No. 5 Results of Drug Release Kinetics Model of Optimized Formulation

Batch	Zero order		First order		Higuchi model		Korsemeyer-pepas
Batch	K	R²	K	R²	K	R²	K	R²
BFC1	12.212	0.9794	0.165	0.9387	39.522	0.9989	0.4807	0.9994
BFC2	5.329	0.9795	0.0684	0.9654	16.774	0.9448	0.1883	0.9169
BFC3	8.8919	0.9796	0.1165	0.9681	22.474	0.9876	0.3288	0.9772
BFC4	7.4333	0.9126	0.0761	0.9679	24.422	0.9684	0.2161	0.9793
BFC5	8.541	0.9719	0.1129	0.9352	27.49	0.9898	0.3280	0.9898
BFC6	6.3191	0.9734	0.0706	0.9851	20.188	0.9769	0.195	0.9418
BFC7	7.8825	0.9354	0.0891	0.9678	25.758	0.9820	0.2539	0.985
BFC8	9.0248	0.9873	0.1288	0.9662	28.816	0.9896	0.3653	0.9751
BFC9	9.5844	0.9664	0.1315	0.9527	30.772	0.9793	0.3690	0.9415

Fig. 6

Table No: 6 Optimized Batches By CCD

Run	Batch	Factor 1 X1 Conc. of Castor oil (ml)	Factor 2 X2 Conc. of Span 80 (ml)	Dependent Variables
Run	Batch	Factor 1 X1 Conc. of Castor oil (ml)	Factor 2 X2 Conc. of Span 80 (ml)	Drug Release (%) Y1
1	LFC1	0.55	6	91.27
2	LFC2	15	10	89.38
3	LFC3	10.4	6	85.39
4	LFC4	9	17.4	88.75
5	LFC5	9	0.51	88.78
6	LFC6	3	2	91.27
7	LFC7	9	6	86.76
8	LFC8	15	2	80.10
9	LFC9	3	10	78.12

4.8 Optimization and Data Analysis of Optimize Capsule-in-Capsule Technology: Using the DoE Software CCD method 9 batches of Capsule-in-Capsule Technology were prepared by taking a different concentration of dependent factor and evaluated using various parameters like % drug release, Drug Content, % Entrapment Efficacy.

Fig. No. 7 : 3-D Surface Graph Showing the Influence of Conc. of Castor Oil (X1), Conc. of Span 80 (X2) on % Drug Release

The % drug release of Glipizide at min varied from 84.63 % to 95.52 %. The results of multiple regression analysis showed that positive value of X1 indicate relationship with response Y1 (% drug release). That is % drug release increases with increase in conc. of Castor oil and increase with slightly increases in conc. Span 80.

Table No :7 Sustained release phase: Glipizide beads

Run	Batch	Factor 1 X1 Con. of Sodium alginate	Factor 2 X2 Conc. of Calcium chloride	Dependent Variables
Run	Batch	Factor 1 X1 Con. of Sodium alginate	Factor 2 X2 Conc. of Calcium chloride	Drug release (%) (Y1)	Entrapment efficacy (%) (Y2)
1	BFC1	1	3.5	97.32	81.75
2	BFC2	3	5	92.62	79.68
3	BFC3	3.41	3.5	94.19	82.12
4	BFC4	2	5.62	93.48	93.13
5	BFC5	2	1.37	92.34	89.34
6	BFC6	1	2	98.16	85.62
7	BFC7	2	3.5	90.16	90.41
8	BFC8	3	2	90.00	78.30
9	BFC9	1	5	89.56	76.06

Fig No.8: 3-D Surface Graph Showing the Influence of Conc. of Sodium Alginate (X1), Conc. of Calcium Chloride (X2) on % Drug Release

% Drug release of Glipizide beads (Y1) = +89.23860 +9.54X1 + (-2.37)X2 +(-0.81)X1X2 +(-1.36)X1²+0.38X2²The % drug release of Glipizide beads at 12 hrs. Varied from 89.56 % to 98.16.87 %. The results of multiple linear regression analysis showed that the coefficients X1 factor bear a positive sign. Therefore, increased in the concentration of X1 to decreased the % drug release. X2 factor bears positive sign. Therefore, increase in the concentration of X2 the drug released slightly increases. Entrapment efficacy (Y2) = +61.06091 +14.2X1 +13.4X2 +1.42X1X2 + (-5.33X1²) + (-2.64X2²) Concerning the Entrapment efficacy, the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a positive sign. Therefore, increase in the concentration of X1 and X2 is expected to increase the Entrapment efficacy.

5. CONCLUSION:

A novel biphasic delivery system was successfully developed these biphasic delivery system is beneficial for diabetes. The immediate releasing liquid and sustained releasing Beads of Glipizide were selected through in-vitro dissolution studies. The Glipizide were characterised for colour, odour, taste and it matches to standard as per COA. The melting point of Glipizide was found to be 205⁰C and it matches to standard value and also confirm by DSC. The drug excipient study was performed by using FTIR and DSC. In Immediate released Phase result shown that with increased in concentration of Castor oil and increased in concentration of Span 80 the release rate gradually increased. The best fast releasing liquid dispersion (LFC-3) and slow releasing beads (BFC-4) of Glipizide were selected through in vitro dissolution studies. Optimized capsule-in-a-capsule formulation released 19.61 at 30 min of drug at the end of 2 hr. and 93.30 % of drug at the end of 12hr. formulation exhibits the best result in drug released Pepas kinetic model These result showed the potential of the novel Capsule-in-capsule technology for biphasic delivery of Glipizide formulation will be used for the treatment of diabetes diseased.

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Received on 26.11.2023 Modified on 23.12.2023

Res. J. Pharma. Dosage Forms and Tech.2024; 16(1):27-34.

DOI: 10.52711/0975-4377.2024.00005