INTRODUCTION:

The capsules which are designed for intestinal delivery by being intact in the stomach are called as enteric capsules and this property is called enteric property. To achieve the intestinal delivery the capsule must be strong enough to resist the acidic environment in the stomach. Apart from the reason that the capsules may affect the gastronomical metabolism, some drugs require past gastronomical delivery to treat some local diseases like ulcerative collitas, irritable bowel syndrome and to absorb polypeptides in the intestine. The endogenous enzymes are less in the colon and the transit time is long which will favor the absorption of polypeptides¹.

The capsule dissolution time cannot be determined exactly in the capsules which are released in the stomach as the residence time is highly irregular and depends on the several factors like the size of the fabricated capsule, fed or fasted state of the stomach etc.

If the colon is the desirable and perfect place for absorption of therapeutic polypeptides, which are orally consumed then there is a compulsory for enteric capsules which can target the colon release and can withstand the acidic gastronomical juices and state of gastronomical duct².

For several decades these enteric properties are delivered to the capsules mainly by coating the hard gelatin capsules using acid resistant chemicals such as anionic polumethacryalates (copolymerasite of methacrylic acid and tither methul methacrylate or ethyly acrylate (Eudragit), cellulose based polymers such as cellulose acetate phthalate (Aquateric) or polyvinyl derivatives such as polyvinyl acetate phthalate, hydroxyl propyl methyl cellulose phthalate, sodium alginate stearic acid etc. These acidic polymers have very low permeability in their unionized state in low pH environments and when they reach high pH environments they ionize and resulting in increase of the permeability. As a result, the capsule erodes and releases the underlying drug. These kind pH variations can be seen in the stomach and intestine respectively³. These enteric coatings showed a great advantage that it is independent of the encapsulated material. This advantage resulted in the decrease in the extent of research to develop a formulation, which is enteric by nature itself irrespective of any enteric coating applied⁴.

Need for enteric capsules:

Gelatin is the major polymer base for manufacturing capsules for many years. These enteric coatings are applied on the surface of these gelatin capsules. However, due to several considerations alternative materials like hypromellose are opted in some specific cases. Hypromellose has several advantages when compared to gelatin capsules regarding their response towards organic coatings, aqueous coatings, storage, structure etc. During recent years, pharmaceutical coating technology has undergone several fundamental changes. The original sugar-coating technique has been largely replaced⁵by film coating processes using aqueous or organic solvents. From the point of view of environmental pollution, safety and cost, aqueous-coating systems are preferred. The application of a film coating on a pharmaceutical dosage form comprises several delicate steps. Equilibrium must be established such that the coating material adheres and coalesces properly upon contact with the surface of the substrate, yet it also must dry rapidly so that core penetration of solvent and dissolved coating material is minimized and agglomeration of core material is prevented. To create the necessary environment for such a process to occur, specialized coating equipment, and optimal processing conditions are mandatory. However, the current coating techniques are characterized by several critical process variables such as spray rate of the coating solution, temperature, pressure and volume of the drying air and equipment dimensions. These critical parameters can cause non-uniformity of the applied coating layer and up scaling problems. Moreover, aqueous-coating systems are not applicable for moisture sensitive active ingredients⁶.

Alginates are complex carbohydrates known as polysaccharides. These carbohydrate polymers are derived from brown seaweeds of the Class Phaeophyceae. Phycocolloid is another term for polysaccharides (e.g., agar, alginates and carrageenan) that are derived from seaweeds⁷. Similar to the structure forming components of cellulose in terrestrial plants, alginates give brown algae, including brown seaweed species, both 48 mechanical strength and flexibility. The main cell wall 49 components of seaweed are anionic polysaccharides: alginates and fucoidans. Algal polysaccharides differ from cellulose in their high sulfate group content, high solubility in water and high 51 content of ionic groups. The algin found in brown algae is present as a mixed salt (sodium and/or potassium, calcium, magnesium) of alginic acid. Alginates are derivatives of alginic acid. Alginate is the conjugate base of alginic acid. Through processing, the water insoluble alginic acid is extracted and various water-soluble alginates can be produced⁸. When extracted from the cell walls of brown algae, alginate forms a gum that is used by the food industry to increase viscosity, as a food thickener and stabilizer, and as an emulsifier. Tragacanth is a natural gum obtained from the dried sap of several species of Middle Eastern legumes the genus Astragalus, including A. adscendens, A. gummifer, A. brachycalyx, and A. tragacantha. Some of these species are known collectively under the common names "goat's thorn" and "locoweed"⁹. The gum is sometimes called Shiraz gum, shiraz, gum elect or gum dragon. The name derives from the Greek words tragos (meaning "goat") and akantha ("thorn"). Iran is the biggest producer of this gum^10,11.

MATERIAL AND METHODS:

Preformulation:

Erythromycin, Sodium Alginate, Shellac, Cellulose acetate phthalate, Poly (methacrylic acid- co- methylacrylate), HPMCP (hypromellose phthalate) from the Innovative Chemical Interchange Pvt. Ltd. Hyderabad; Carrageen and tragacanth from Sigma Aldrich India was used in this study.

Selection of polymer:

From the literature review following enteric coating polymers were selected

· Shellac

· Cellulose acetate phthalate

· Poly (methacrylic acid- co- methylacrylate)

· HPMCP (hypromellose phthalate)

· Sodium alginate

Shellac dissolves only above pH 7 were the intestinal pH is below 6.8. Cellulose acetate phthalate dissolves in pH 6.2 but it is not resistible to acid pH which causes degradation of capsule shell. Poly (methacrylic acid- co- methylacrylate) dissolution pH is 7.5 to 7.8 which is not suitable for intestinal pH. HPMCP dissolves in pH 4.5 to 5.5 where it will dissolves before entering intestine. Sodium alginate dissolves in pH 2 to 7 which makes it dissolves in intestinal pH and also resistant to intestinal pH. With the addition of the glycerol the solubility in acidic pH becomes low and solubility in alkaline pH increases.

Polymer characterization:

Solubility in water:

1g of the samples (Sodium alginate, Carrageenan and Tragacanth) was taken and kept in 50ml of water to check solubility of polymers¹².

Calibration curve

Preparation of standard stock solution:

50mg of pure erythromycin was accurately weighed and transferred to 50ml of volumetric flask. Drug was dissolved in ethanol and volume was made up to 50ml. The concentration of drug was 1mg/ml. 2.5ml of this solution was taken in a 25ml volumetric flask and volume was made up to the mark with ethanol. Thus erythromycin of strength 100µg/ml was obtained¹³.

Procedure for plotting calibration curve of pure drug:

From the standard stock solution 0.5ml, 1ml, 1.5ml, 2 ml, 2.5ml dilutions were made in 10ml volumetric flask and volume was made up to the mark with ethanol to obtain concentration in range of 5-25µg/ml. The spectra were recorded, absorbance was measured at 480nm by UV spectrophotometer and calibration curve was plotted.

Preparation of films:

The sodium alginate solution was prepared as following: Measure 95ml of water and heat up to 70֯ C and add 5g of sodium alginate then glycerol was added. 20ml of prepared solution was poured into the Petri dish and dried in room temperature for 24 h.

The sodium alginate admixture solution was prepared as following; Measure 94ml of water and heat up to 70°C followed by addition 5g of sodium alginate. To this, carrageen solution was added. Add tragacanth powder (0.5gm or 1g). This mixture is heated to 70-800°C for 60-80 min with continues stirring. To this glycerol was added.¹⁴The above mixture 20ml was casted in the Petri dish and dried at in room temperature for 24 h. Carrageen solution was prepared by taking 0.06g of KCl and dissolve in water to this, carrageen (0.3 to 0.6g) was added which increased the solubility of carrageen.

Characterization of films:

Solubility in water: Solubility studies of the sodium alginate and sodium alginate admixture (tragacanth and carrageen) films were carried out. The solubility of the films in water was determined by following method. Pieces of films (2×3cm) were kept in desiccators for a week then they were weighed and kept into beakers with 80 ml deionized water. The remaining piece of film after 1 h was filtered, followed by oven drying at 600 ºC until constant weight.

% Solubility= (Final weight-Initial weight)/(Initial weight) ×100

Solubility in acidic and alkali pH: From the literature review we got to know that the soluble pH of sodium alginate is between pH 2 to pH 7. The solubility of the films in different pH were determined by following method, Pieces of films (2×3cm) were kept in a desiccators for a week. Samples were weighed and kept into beakers with 80 ml buffer of different pH (pH 1.2 and pH 6.8)¹⁵.

Thickness of film:

Thickness of the film is determined by vernier caliper. Film of 2×3cm was used for the thickness determination¹⁶.

Test of swelling degree:

The test of swelling degree was performed by immersing a sample in 100ml of distilled water for 1 h with two replications. The sample which has absorbed water was further separated from water with filter paper, then weighed to determine its mass¹⁷. The test of swelling degree was carried out at 37±0.1ºC. The magnitude of swelling degree can be determined by

Q = (Wt - Wo)/ Wo×100

Where,

Q = swelling degree, W_t= mass of polymer that has absorbed water (g), W_o= mass of the polymer before absorbing water)

Preparation of capsules:

After the obtaining optimal ratio (w/w) of alginate, carrageen and tragacanth, the powder mixture of 5% sodium alginate, 0.6% carrageen is taken in a glass beaker added with distilled water gradually to form a colloidal solution. The mixture was kept stirred for five minutes at room temperature. Then, the mixture solution was heated in a water bath for approximately 60–90 min at a temperature range of 70–800ºC. The heating process was terminated when a solution of the mixture has become homogeneous. The container of the mixture was covered with aluminum foil during heating. Preparation was done by dipping a pin that has been lubricated by used cooking oil before dipping. Material attached to the pin bar was dried at room temperature to form the desired capsule¹⁸.

Characterization of capsules:

Dissolution kinetics:

Dissolution is the release process of drug substance from the dosage and dissolves in the solvent medium. The dissolution test was conducted to determine the diffusion of the drug over time in an environment that represents the condition of the body. For testing the dissolution of enteric capsules, experiment should be done in acidic medium (pH 1.5 to 3.5) followed by alkali medium (pH 6 to 7.5). In this study, the capsules were tested in HCl solution with acidity variation to determine the ability of dissolution. The pH variation used in this study is based on the pH present in the human body and refers to the WHO-USP standard is pH 1.2 (stomach), and pH 6.8 (duodenum).

In-vitro release is carried out using USP Apparatus type II (Electro Lab, Mumbai, India) at 50rpm. The dissolution was done by taking 900ml of buffers of different pH i.e., 1.2 and 6.4 in different beakers and the temperature was maintained at 37±0.5°C. The drug release at different time intervals was measured by UV visible spectrophotometer (Shimadzu, Japan) at 480 nm.

Drug release (%) = mass of drug that has been released/initial mass of drug*100%

RESULTS AND DISCUSSION:

Pre formulation studies:

Selection of polymer:

Based on the above mentioned literature sodium alginate was short listed. Based on their enteric property polymer was short listed. Polymers were rejected as due to the solubility barrier in alkali pH. By taking sodium alginate as a enteric polymer the selection of other excipients was done. Other excipients include thickening agent and a co gelling agent. Handoko Darmokoesoemo (2017) mentioned the synergetic effect of the k- carrageen with the sodium alginate. Tragacanth was taken as thickening agents²⁰.

Characterization of polymer:

Solubility in water:

Sodium Alginate is soluble in hot water, carrageen’s solubility based on Cl^- ion concentration and Tragacanth is soluble in both hot and cold water.

Calibration curve:

Erythromycin was dissolved in ethanol at required dilution and the absorbance observed were tabulated in table 1

Table.1 Calibration of erythromycin

Sl. No	Concentration µg/ml	Absorbance
1	5	0.044
2	10	0.083
3	15	0.127
4	20	0.164
5	25	0.201

Fig.1 Calibration curve of erythromycin.

Calibration curve was plotted using the observed absorbance in y axis and the concentration of the drug in X axis. Linearity was observed with a R²value of 0.999.

Preparation of film:

Sodium alginate admixture solution of different concentrations were made to observe the capsule forming ability of the solutions

Table.2 Different concentrations of different polymers

Sl. No	Sodium alginate (w/v)	Carrageen (w/v)	Tragacanth (w/v)
F1	5%	0	0
F2	5%	0.3%	0
F3	5%	0.4%	0
F4	5%	0.5%	0
F5	5%	0.6%	0
F6	5%	0.3%	0.5%
F7	5%	0.4%	0.5%
F8	5%	0.5%	0.5%
F9	5%	0.6%	0.5%
F10	5%	0.3%	1%
F11	5%	0.4%	1%
F12	5%	0.5%	1%
F13	5%	0.6%	1%

F1 film with sodium alginate was thin, the thickness of film was improved with increasing the volume of solution. To improve the thickness of film carrageen was added, carrageen solubility is based on amount of Cl^-ion presents it the medium. The concentrations of κ-carrageenan ranged from 1 to 0.1%, with corresponding KCl concentrations ranging from 0 to 0.11 according method described by Fakharian et al. (2015). In F2, F3, F4, F5 films, F5 film had shown films with increased thickness. Further optimization is done to increase the thickness of the film while decreasing the amount of solution used, for this tragacanth was added to other formulations. Two concentrations (0.5% and 1%) of tragacanth was added to the formulations with different concentrations of carrageen to obtain the correct formula for films F6, F7, F8, F9 films with 0.5% tragacanth has no effect on film thickness but films of F10, F11, F12 films has an improved the thickness F13 films has shown the improved film thickness with less amount of solution. The obtained films are opaque.

Fig 2. Sodium alginate film

Fig 3. Sodium alginate admixture film.

Characterization of films:

1. Solubility in water:

Sodium Alginate was 84 % soluble in water whereas the admixture of Sodium alginate, Carrageen, and tragacanth was 90% soluble in water.

% Solubility of sodium alginate film=

(0.01-0.11)/0.11×100=84 %

% Solubility of admixture film =

(0.01-0.126)/0.126×100=92 %

2. Solubility in different Ph:

Table.3 Solubility of films in different pH

Sl. N o	Sample	Solubility
1	Sodium alginate	Soluble in pH 1.2 and 6.4
2	Sodium alginate, Carrageen, and tragacanth	Solubility in pH 1.2 and 6.4
3	Sodium alginate, Carrageen, and tragacanth with glycerol 0.75%	not soluble in pH1.2 and soluble in pH 6.4

By preparing films with three substances solubility of film is observed in both acidic and alkali medium. But the pH dependent solubility happens with the addition of glycerol in specific amount. Where the capsules with no glycerol or less than 0.25 ml glycerol is soluble in acidic conditions and capsules having glycerol concentration above 0.5 ml are not dissolved in acidic pH but dissolves in alkali pH.

3. Thickness:

Thickness of the 2 × 3cm sodium alginate film was found to be 0.5 mm

Thickness of 2 × 3 cm sodium alginate admixture film was found to be 1mm.

4. The test of swelling degree:

This analysis performed on each type of film (for each type done as much as 6 times). Samples that have absorbed water at predetermined time separated from the solvent (water) using filter paper and then weighed to determine its mass. Before the immersion, the film weighed first in order to determine the initial mass. The analysis of swelling degree conducted at room temperature and without stirring. The analysis results of swelling degree of film shell from alginate, Tragacanth-carrageenan can be seen in Table 4. In this case, glycerol which acts as plasticizer relaxes the intermolecular interaction of alginate-carrageenan thus softening gel that initially more viscous. The stretching due to the addition of the plasticizer causes the increasing swelling degree along with the increasing amount of glycerol. The swelling degree of film can affect the dissolution process. With the swelling degree is increasing then it can make the diffusion process of the drug becomes more slow so that the drug cannot be released perfectly. The occurrence of swelling causes the increase of distance on polymer chains so that the resulting interaction between the solvent and the compounds present in the polymer. The differences in the swelling degree that occurs can be utilized in medical applications according to the needs. For example, gelatin films that are more easily broken can be applied as film for ulcer drug. Another example is film f₂ that have a relatively small of swelling degree can be applied as film for the needs of drug that can release on the digestive system in the intestine, such as colon cancer.

Table 4. Swelling degree of formulated films

Swelling degree of gelatin films			The swelling degree of film (without glycerol).			The swelling degree of film (glycerol of 0.75 ml)
Wo (g)	Wt (g)	Q (%)	Wo (g)	Wt (g)	Q (%)	Wo (g)	Wt (g)	Q (%)
0.0957	0.1897	98.22	0.0850	0.4504	429.9	0.1261	0.8906	606.26
0.0909	0.3818	320.0	0.0952	0.2562	169.1	0.1019	0.9297	821.36
0.0954	0.1946	104.0	0.0950	0.8174	760.4	0.1028	0.8875	763.32
0.0958	0.2088	119.8	0.1101	0.7348	567.4	0.1103	0.9010	716.86
0.1342	0.2988	122.6	0.0943	0.4212	346.7	0.1117	0.9103	714.95
0.0949	0.1976	108.2	0.0762	0.4121	440.8	0.1020	0.8912	773.72
Average	145.02		452.4			731.22
Standard deviation	86.00475		200.0806			73.530

* W₀ is mass of film before immersion, W_t is mass of film after immersion, Q is swelling degree of film.

Fig.4 Sodium alginate films before swelling

Fig.5 Sodium alginate films after swelling

Preparation of capsules:

The optimized composition ratio of alginate, carrageenans, tragacanth and glycerol is done in order to obtain the characteristics of the capsule shell according to industrial standards. The gel formation from mixture of alginate, Tragacanth and carrageenan due to the hydrophobic group of long-chain polysaccharide. This leads to the tendency of alginate and carrageenans to interact intermolecular against each other than against water. The addition of glycerol as plasticizer causes the mixture which was originally viscous turn out to be more lenient. This is supported by the large number of –OH groups in glycerol which increase the hydrogen bond between the mixtures of alginate carrageenans in water. The purpose of varying the added glycerol is to determine the effect of the dissolution process, swelling, and tensile test on the alginate, Tragacanth-carrageenan capsule. The mixture is stirred continuously for approximately five minutes at room temperature. During the stirring process is done then the mixture of alginate and carrageenan will form gel. Then performed the heating against mixture of alginate, tragacanth and carrageenans that has been added to the glycerol according to the composition which has been determined. The heating is carried out in water bath at temperature maintained in the range of 70–80 ⁰C for approximately 60–90 min. At this temperature, the mixture began forming homogeneous liquid with cloudy white color. The heating is performed should be maintained at temperature range of 70–80 ⁰C. If the temperature is below the range then the mixture of alginate, Tragacanth and carrageenan will harden before printing and solution mixture become not completely homogeneous. Whereas if the temperature is allowed to exceed the predetermined range, the mixed solution of alginate, Trgacanth and carrageenan will be very dilute so hard to do the dipping. The mixture is poured on dipping bath which has been heated to temperature range 60-80 ⁰C. This is done so that the mixture of alginate-carrageenan is easy to do the dipping and keep the temperature when the heating stopped. Preparation is done by dipping a pin that has a size of zero and has been lubricated with soybean oil lubricant. The obtained capsule shell is dried at room temperature to form the desired capsule shell. In this study sodium alginate admixiture (tragacanth and carrageenans) capsules with 0.75 ml glycerol and without glycerol were prepared. Both the capsule are translucent in nature with size of 3cm.

Characterization of capsules:

Analysis of dissolution kinetics:

Generally at pH 1.2 capsule shells with glycerol show the kinetics of dissolution profiles are linear. At the time of 80 min, the concentration of erythromycin increased up to 37%. While the capsule C₂ with 0.75 ml of glycerol shown no dissolution up to 80 min. This indicates that the application of drug delivery carrier for capsules shell from alginate, tragacanth-carrageenan without glycerol as the plasticizer takes approximately 80 min to be able to release in the stomach that have pH 1.2. Greater the ability of the drug dissolution indicates that the bioavailability of the material as a drug delivery carrier becomes higher. From the dissolution results at pH 1.2 it is known that the capsule shell (without glycerol) is the most stable capsule compared with the other capsule shell (with glycerol) at pH 1.2. The variation of glycerol that have been added to the capsules of alginate admixture (tragacanth and carrageen) also greatly influences the dissolution process, which shows that type 2 capsule with the addition glycerol of 0.75 ml forming a linear line at pH 6.8 when compared with other type of capsule with no glycerol. This is because with the increasing amount of glycerol added then the process of drug diffusion runs more slowly and unstable. The slowing of the diffusion process can also be affected by the swelling value of the capsule where the swelling value increases with the addition of glycerol. This can be seen from the dissolution results of type C₂ capsules that have been added relatively large amounts of glycerol which can lead to inhibition of the diffusion process of drugs present in the capsule. The slow process of diffusion in type C₂ capsules can also be caused because capsule C₂ have high swelling values. Glycerol that acts as a plasticizer causes the number of intermolecular bonds that occur to be increasing. This is why it can affect the value of swelling and cause the dissolution process to be slow. The dissolution of capsule C₂ from the data it can be seen that in general the capsule C₂ dissolved more than 50 % in 20 min and completely dissolved in 80 min. This shows that the drug delivery carrier for the capsule shell made from alginate, tragacanth-carrageenan with the addition of glycerol as a plasticizer is very easy dissolved at pH 6.8 or can be easily dissolved in alkaline conditions. It can be caused by the structure of alginate and carrageenan are predominantly have acidic properties. This is because the alginate consists of mannuronic acid and glucuronic acid, while carrageenans have the sulfonate group. The existence of the acid groups that dominate at alginate-carrageenan causes the capsule shell can easily undergo the neutralization reaction at more alkaline conditions so that the disintegration process becomes faster than the dissolution at pH 1.2. From the results of the dissolution that has been done can be seen that the capsule C₂ has low solubility rate in 1.2 pH and also have high solubility rate in alkali pH.

Dissolution curve of erythromycin capsules:

Table.5 Dissolution curve of erythromycin capsules obtained from the In vitro drug dissolution studies in USP type 2 Apparatus in various dissolution media.

*In vitro* drug dissolution studies	Time ( min)	10	20	40	60	80
Dissolution of capsule C1 in pH 1.2	% Drug Release	2	13.5	26	29	37
Dissolution of capsule C2 (with 0.75ml glycerol in capsule shell) in pH 1.2	% Drug Release	0	0	0	0	0
Dissolution of capsule C2 (with 0.75ml glycerol in capsule shell) at 6.8 pH	% Drug Release	45	54	81	90	98.35

Fig.6 Dissolution curve of erythromycin capsules at pH 6.8. NOTE: there was no drug release at pH 1.2.

Fig.7 Capsule before dissolution

Fig.8 Capsule after dissolution

CONCLUSION:

From the above summary we can conclude that the capsules consist of sodium alginate, carrageen and tragacanth, having enteric property which is obtained by the addition of glycerol.

ACKNOWLEDGEMENT:

The authors would like to thank Department of Science and Technology- fund for improvement of science and technology infrastructure in Universities and Higher Educational Institutions (DST- FIST), New Delhi for their infrastructure support to our department.

CONFLICT OF INTEREST:

The authors declare there is no conflict of interest.

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Received on 23.08.2019 Modified on 18.10.2019

Research J. Pharm. and Tech. 2020; 13(8):3603-3609.

DOI: 10.5958/0974-360X.2020.00637.X