Description:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of pharmaceuticals, and in specific relates to a method of preparation of modified natural karaya gum or gum sterculia with specific substitution pattern for its application in the field of a pharmaceutical formulation for sustained or controlled or delayed or extended release drug delivery systems.
Background of the invention:
[0002] Natural excipients are gaining popularity in the pharmaceutical industry due to the advantages over synthetic polymers which include biodegradability, biocompatibility, and lower cost. Karaya gum, a natural gum extracted from the Sterculia urens tree, is one such excipient with potential applications in various dosage forms. However, karaya gum has some drawbacks that include high swelling nature and viscosity, which can lead to uncontrolled drug release.

[0003] Generally, sustained release compositions allow administration of an effective dose of a drug over an extended period of time. Sustained release is advantageous since patient's side effects arising out of administering an immediate release therapy may be reduced. Sustained or prolonged-release dosage forms of various drugs are known in the art. Conventional sustained release dosage forms include the use of a polymer matrix, as well as complexing the drug with an ion exchange resin forming a drug-ion exchange resin complex particle. After administration, the drug is slowly released from the complex or matrix over time, thereby providing a continuous delivery of drug to the patient.

[0004] Conventional pharmaceutical sustained release compositions often include polymers such as hydroxylproplyl methylcellulose, sodium carboxy methylcellulose, hydroxylpropyl cellulose, methyl cellulose, chitosan, and natural gums to sustain drug delivery. However, synthetic polymers are often associated with toxicity, high cost, environmental problems, and manufacturing issues. Natural polymers that include karaya gum have limited pharmaceutical acceptance due to their uncontrolled swelling and thick gel formation, which can interrupt drug diffusion and lead to variations in drug release.

[0005] Furthermore, several patents and research papers have described methods for modifying natural gums for use in pharmaceutical formulations. For example, an existing prior art US3989683A discloses a method for treating karaya gum to improve its extrusion characteristics and rheological stability. US20110136921A1 discloses a sustained release composition comprising spray-dried particles of karaya gum and other excipients. WO2002102415 discloses a solid gastric floating dosage form comprising karaya gum and other excipients.

[0006] WO2017013682A1 discloses a co-processed polymer of karaya gum and other polysaccharides for use in pharmaceutical dosage forms. A research paper by Moin et al. (2010) describes the formulation of sustained-release Diltiazem matrix tablets using karaya gum alone or in combination with other excipients. However, some conventional methods involve complex chemical processes or require specialized equipment. Some methods are expensive to implement. Some methods do not provide sufficient control over the drug release profile.

[0007] Therefore, there is a need for a simple and effective method for modifying karaya gum to achieve controlled drug release. There is also a need for a composition that is biodegradable, biocompatible, nontoxic, and eco-friendly. There is also a need for a method that changes the structure of the karaya gum, which is less prone to swelling and forms a more porous gel structure. There is also a need for a method that uses a natural and biodegradable polymer, making it safe for use in humans. There is also a need for a method that has the potential to be a commercially viable product. There is also a need for a method that attains better bioavailability of the drug and enables the product free from microbial contamination.
Objectives of the invention:
[0008] The primary objective of the invention is to provide a method of preparation of modified or derivatized natural karaya gum for controlled or delayed or sustained or extended release drug delivery systems.

[0009] Another objective of the invention is to provide a composition that is biodegradable, biocompatible, nontoxic, and eco-friendly.

[0010] The other objective of the invention is to provide a method that modifies the structure of the karaya gum, limiting uncontrolled hydration and forms a more porous gel structure.

[0011] The other objective of the invention is to provide a new natural and biodegradable polymer, making it safe for use in humans.

[0012] Yet another objective of the invention is to provide a method to modify karaya that has the potential to be a commercially viable product.

[0013] Further objective of the invention is to provide a method that improves the dispersability of the specific gum and reducing the rheological fluctuations.
Summary of the invention:
[0014] The present disclosure proposes a method for preparation of etherification-derived hydroxypropyl karaya gum for sustained-release drug delivery applications. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0015] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a method of preparation of modified natural karaya gum or gum sterculia with specific substitution pattern for its application in the field of pharmaceutical formulation for sustained or controlled or delayed or extended release drug delivery systems.

[0016] According to an aspect, the invention provides a method of preparation of hydroxypropyl karaya gum. At one step, karaya gum is dissolved in a solvent system to obtain a karaya gum mixture. At another step, propylene oxide is added in the karaya gum mixture in the presence of at least one catalyst to form a reaction mixture. At another step, the reaction mixture is stirred in a temperature range of 30°C to 40°C for a time period of 2 to 6 hours. At another step, the reaction mixture is neutralized with an acid that includes hydrochloric acid (HCl), hydrosulphuric acid (H2SO4), thereby precipitating the hydroxypropyl karaya gum with an organic solvent like methanol, or ethanol. At another step, the hydroxypropyl karaya gum is separated from the reaction mixture.

[0017] In one embodiment, in specific, the propylene oxide is added in the karaya gum mixture under controlled conditions of a temperature varies between 30°C and 40°C and a reaction time varies between 2 hours and 6 hours. The catalyst comprises sodium hydroxide or potassium hydroxide, which is at least 3% by weight of the reaction mixture. The solvent system includes a mixture of isopropyl alcohol and water. The solvent system comprises at least 75% of isopropyl alcohol and 25% of water (v/v).

[0018] In one embodiment, HP-karaya is prepared with different levels of hydroxypropylation, varies between HPK16 and HPK48, depending on different concentrations of the propylene oxide used for the preparation of the HP-karaya. The propylene oxide concentration increases, causing an increase in the degree of hydroxypropylation in the HP-karaya. Here, the propylene oxide concentration varies between 16% and 48% by weight, resulting in different degrees of hydroxypropylation in the HP-karaya. In specific, the degrees varies between 5% and 15% by weight of the HP-karaya.

[0019] The hydroxypropyl karaya gum with 32% propylene oxide is safe and non-toxic at doses below 2000 mg/kg, thereby consequently indicating the safety and nontoxicity of lower percentage HP-karaya as well. The HPK32 is clear of fungal and bacterial contamination including harmful bacteria. The hydroxypropyl karaya gum (HPK32) exhibits sustained or controlled or extended or delayed drug release for 12 hours in acidic and alkaline conditions.

[0020] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0021] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.

[0022] FIG. 1 illustrates a perspective view of reaction setup of preparation process of hydroxypropyl karaya, in accordance of an exemplary embodiment of the invention.

[0023] FIG. 2 illustrates a flowchart of a method of preparation of hydroxypropyl karaya gum, in accordance of an exemplary embodiment of the invention.

[0024] FIG. 3 illustrates a graphical representation of percentage hydroxypropylation of karaya gum at varying monomer concentrations, in accordance of an exemplary embodiment of the invention.

[0025] FIGs. 4A-4F illustrate graphical representations of the structural analysis and respective spectra of karaya gum and all forms of HP-karaya (HPK16, HPK24, HPK32, HPK40 and HPK48) that are obtained in the preparation process at different monomer concentrations using Fourier transform infrared (FTIR) spectroscopy, in accordance of an exemplary embodiment of the invention.
Detailed invention disclosure:
[0026] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.

[0027] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a method of preparation of modified natural karaya gum or gum sterculia with specific substitution pattern for its application in the field of pharmaceutical formulation for controlled or delayed or extended release drug delivery systems.

[0028] According to an exemplary embodiment of the invention, FIG. 1 refers to a perspective view of reaction setup of preparation process of hydroxypropyl karaya. The proposed method of preparation of modified or derivatized natural karaya gum aids in controlled or delayed or sustained or extended release drug delivery systems. The proposed method comprises a composition that is biodegradable, biocompatible, nontoxic, and eco-friendly. The proposed method modifies the structure of the karaya gum, limiting uncontrolled hydration and forms a more porous gel structure.

[0029] The proposed method provides a new natural and biodegradable polymer, making it safe for use in humans. The proposed method to modify karaya gum that has the potential to be a commercially viable product. The proposed method improves the dispersability of the specific gum and reducing the rheological fluctuations. A schematic representation of hydroxypropylation mechanism is shown in the below equation.

[0030] In one embodiment herein, initially, 20 grams of powdered karaya gum passed through a sieve is weighed and added to 75 ml of isopropyl alcohol that is taken in a conical flask 104, thereby forming a reaction mixture. Next, the reaction mixture is thoroughly mixed to form a uniform dispersion. Next, 25 ml of distilled water is added to the reaction mixture through an inlet 106. Next, 0.6 grams of sodium hydroxide is added and mixed for 30 minutes to form slurry. After 30 minutes of mixing, the chemical reaction is initiated by adding different weight percentages of propylene oxide calculated based on the weight of gum karaya to the obtained slurry (as shown in the Table 1).

[0031] Next, the reaction is carried out for 2-6 hours in a conical flask 104 that is fitted to a condenser 108 and placed on a temperature control magnetic stirrer 102 as shown in the FIG.1. The temperature is maintained between 30°C to 40°C throughout the reaction with continuous stirring at 200 revolutions per minute (rpm). After 2-6 hours, the excess alkali is neutralized by adding 0.5 N HCl to pH 7 by a pH meter. Next, the product formed is washed with water and then precipitated with methanol. Finally, the precipitate collected is dried in a hot air oven at a temperature less than 50°C to a constant weight. The final weight of each product is recorded to calculate the percentage yield. The reaction procedure is repeated at different monomer concentrations (as shown in the Table 1).

[0032] In one embodiment herein, the hydroxypropyl group is introduced onto karaya gum by treating with different concentrations of the propylene oxide. The percentage yield calculated from the precipitated product is (as shown in the Table 1).

[0033] Table 1 shows percentage yield of hydroxypropyl karaya (HP-karaya).

[0034] Table 1:
HP-karaya grade Percentage yield (%w/w)
HPK16 85.47%
HPK24 78.02%
HPK32 71.96%
HPK40 64.60%
HPK48 62.06%

[0035] Here, the percentage yield decreased with high propylene oxide concentrations.

[0036] According to an exemplary embodiment of the invention, FIG. 2 refers to a flow chart 200 of a method of preparation of hydroxypropyl karaya gum. At step 202, karaya gum is dissolved in a solvent system to obtain a karaya gum mixture. At step 204, propylene oxide is added in the karaya gum mixture in the presence of at least one catalyst to form a reaction mixture. At step 206, the reaction mixture is stirred at a temperature of at least 30°C to 40°C for a time period of 2 to 6 hours. At step 208, the reaction mixture is neutralized with an acid that includes hydrochloric acid (HCl), hydrosulphuric acid (H2SO4), thereby precipitating the hydroxypropyl karaya gum with an organic solvent like methanol, or ethanol. At step 210, the hydroxypropyl karaya gum is separated from the reaction mixture.

[0037] In one embodiment, in specific, the propylene oxide is added in the karaya gum mixture under controlled conditions of a temperature varies between 30°C and 40°C and a reaction time varies between 2 hours and 6 hours. The catalyst comprises sodium hydroxide includes sodium hydroxide or potassium hydroxide, which is at least 3% by weight of the reaction mixture. The solvent system includes a mixture of isopropyl alcohol and water. The solvent system comprises at least 75% of isopropyl alcohol and 25% of water (v/v).

[0038] In one embodiment herein, HP-karaya is prepared with different levels of hydroxypropylation, varies between HPK16 and HPK48, depending on different concentrations of the propylene oxide used for the preparation of the HP-karaya. The propylene oxide concentration increases, causing an increase in the degree of hydroxypropylation in the HP-karaya. Here, the propylene oxide concentration varies between 16% and 48% by weight, resulting in different degrees of hydroxypropylation in the HP-karaya. In specific, the degrees varies between 5% and 15% by weight of the HP-karaya.

[0039] The HPK32 is clear of fungal and bacterial contamination including harmful bacteria. The hydroxypropyl karaya gum with 32% propylene oxide is safe and non-toxic at doses below 2000 mg/kg, thereby consequently indicating the safety and nontoxicity of lower percentage HP-karaya as well. The hydroxypropyl karaya gum (HPK32) exhibits sustained or controlled or extended or delayed drug release for 12 hours in acidic and alkaline conditions.

[0040] According to an exemplary embodiment of the invention, FIG. 3 refers to a graphical representation 300 that represents percentage hydroxypropylation of karaya gum at varying monomer concentrations. The percentage hydroxypropylation in the HP-karaya is increased with increase in propylene oxide monomer concentration indicating the formation of different forms of HP-karaya. The percentage hydroxypropylation is observed in the range of 5.05 to 14.56% w/w. However, no linear proportionality is observed between hydroxypropylation and monomer concentration as shown in the FIG. 3.

[0041] Table 2 shows percentage hydroxypropylation in different forms of HP-karaya.

[0042] Table 2:
Formulation Monomer concentration
(% w/w) Hydroxypropyl group (% w/w)
(mean±s.d., n=3)
HPK16 16 5.05±0.32
HPK24 24 6.98±0.30
HPK32 32 13.57±0.26
HPK40 40 13.96±0.22
HPK48 48 14.56±0.13

[0043] A significant increase in percentage hydroxypropylation is observed on increasing the monomer concentration from 24% w/w to 32% w/w, which is from 6.98±0.50% w/w to 13.57±0.26% w/w. Further rise in monomer concentration has shown a narrow increase in percentage hydroxypropylation from 13.57±0.26% w/w to 14.35±0.23 w/w.

[0044] In one embodiment herein, the statistical analysis of percentage hydroxypropylation of HP-karaya (p<0.05) using one way ANOVA is represented as shown in Table 3.

[0045] Table 3:
Source of Variation Sum of squares Degree of freedom Mean sum of squares F-value P-value F critical
Between Groups 238.18 4 59.54 888.9 1.04e-12 3.478
Within Groups 0.669 10 0.067
Total 238.856 14

[0046] Null hypothesis (H0) is considered to be no significant difference between each grade of HP-karaya. Total treatments (N) is 5, and number of trials in each group (n) is 3. Degree of freedom between groups is 4 and within groups is 10. Table value is 3.47. Here, the calculated F value is greater than the table value (3.47) at a 5% significance level and hence the null hypothesis is rejected and the alternative hypothesis is accepted, indicating a significant difference between five products prepared.Furthermore, to find specific difference between the means, Duncan’s test is employed for further analysis and the results are shown in Table 4.

[0047] The Table 4 shows statistical analysis of percentage hydroxypropylation of HP-karaya using Ducan’s test (p<0.05).

[0048] Table 4:
Conclusion HP-karaya derivatives
Significant difference in percentage hydroxypropylation HPK16-HPK24; HPK16-HPK32; HPK16-HPK40; HPK16-HPK48; HPK24-HPK32; HPK24-HPK40; HPK24-HPK48; HPK32-HPK48; HPK40-HPK48
Non-significant difference in percentage hydroxypropylation HPK32-HPK40

[0049] Here, a significant difference in hydroxypropylation is observed on increasing the propylene oxide concentration from 16% w/w to 32% w/w (i.e between HPK16, HPK24 and HPK32). While there is no significant increase between HPK32 and HPK40 indicating that propylene oxide concentration of 32% w/w and 40% w/w produced similar percentage hydroxypropylation in HP-karaya, 48% w/w (HPK48) propylene oxide concentration has significantly higher hydroxypropylation than 32% w/w (HPK32).

[0050] In one embodiment herein, the potential of HPK32 as a release retardant is validated using theophylline as a model drug by developing theophylline-controlled release tablets. The hydroxypropyl karaya gum (HPK32) is safe and non-toxic at doses below 2000 mg/kg, thereby consequently indicating the safety and nontoxicity of lower percentage HP-karaya as well. The hydroxypropyl karaya gum (HPK32) is clear of fungal and bacterial contamination including harmful bacteria. The hydroxypropyl karaya gum (HPK32) exhibits sustained or controlled or extended or delayed drug release for 12 hours in acidic and alkaline conditions.

[0051] According to another exemplary embodiment of the invention, FIGs.4A-4F refer to graphical representation of the structural analysis and respective spectra of karaya gum and all forms of HP-karaya (HPK16, HPK24, HPK32, HPK40 and HPK48) that are obtained in the preparation process at different monomer concentrations using Fourier transform infrared (FTIR) spectroscopy. FTIR spectroscopy provides a molecular vibrational spectrum which is a method concerned with the identification of the chemical composition of compounds through functional group analysis and is sensitive to structural changes.

[0052] In one embodiment herein, the suggested structure of karaya gum includes the main chain of alternating a-D-galacturonic acid and a-L-rhamnose residues with D-galactose and D-glucuronic acid substituted through hydroxyl groups. Karaya gum is an acetylated gum with 8% acetyl groups. The C=O stretch of the acetyl group gave peaks in the range of 1750-1725 cm-1 in karaya gum. Intermolecular bonding of the gum broadened the –OH band at 3550-3200 cm-1. C-H of alkyl groups formed bands at 3000-2840 cm-1 and 1385-1380 cm-1 by stretching and bending vibrations.

[0053] Bands characteristic of –COOH functional group are observed in the range of 1420-1300 cm-1 due to uronic acid form of galactose and glucose moieties present in the karaya gum. Stretch at 1150-1050 cm-1 implies the C-O-C asymmetric stretch (glycosidic bond) as shown in the FIG. 1A. All the characteristic bands of karaya gum are retained in all the forms of HP-karaya indicates that the structure of karaya gum is preserved even on chemical treatment of gum with propylene oxide.

[0054] In one embodiment herein, a glycosidic bond in polysaccharides is a linkage between the hemiacetal group of a monomer and the hydroxyl group of another monomer. A glycosidic bond is formed by releasing a water molecule and making an O-linkage between the two molecules, while ether linkage involves an oxygen atom linking two alkyl groups. Therefore, the glycosidic bond contains ether linkage and can produce peaks in the range of 1150-1050 cm-1. Hence the ether bond formation on hydroxypropylation may not indicate a change in FTIR spectra. However, along with the reproduction of glycosidic peaks at 1148 and 1042 cm-1, a new peak with intensity increase produced at 1123 cm-1 in all the forms of HP-karaya comparative to karaya gum, which is due to the presence of hydroxypropyl group in the HP-karaya gums.

[0055] The change in CH groups is indicated in the FTIR spectra. CH bending and rocking vibrations are seen at 1415 cm-1 and 1378 cm-1 respectively. On observing the spectrum of karaya gum (as shown in the FIG. 4A), the stretch at 1415.88 and 1378 cm-1 are of the same intensity. Later, upon hydroxypropylation, a change in CH peaks is observed and relative intensities are changed. The intensity of CH bending vibrations has increased in all the forms of HP-karaya.

[0056] In one embodiment herein, HPK48 has shown decreased intensity of functional peaks of karaya gum. The -C=O stretching of ester at 1730.12 cm-1, C=C alkenyl stretching at 1631.79 cm-1, carboxylate stretching at 1417.51 cm-1 and -C-H bending of alkane at 1378.47 cm-1, C-O stretch of ester bond at 1254.04 cm-1 and C-O-C alky substituted ether stretching at 1148.39 cm-1. The intensity decrease is not relatively uniform throughout the spectrum is observed from the spectrum. Therefore, the possibility of intensity decrease due to less sample amount during analysis can be ruled out and the change may be due to alteration in the main structure of karaya gum. The -OH band at 3420.50 cm-1 also has narrowed drastically in HPK48 indicating a high reduction in intermolecular bonding. In addition, HPK48 is not studied for further evaluation to avoid unreliable conclusions from the observations of the FTIR spectrum as shown in the FIG. 4F.

[0057] In one embodiment herein, from the FTIR spectroscopy analysis results and studies, the hydroxypropyl group addition has occurred in all the synthesized HP-karaya gum, certainly at different percentages and also that other than the exempted HPK48; HPK40 and HPK32 have the highest hydroxypropylation. However, there is no significant difference between percentage hydroxypropylation of HPK32 and HPK40 is observed from the Duncan test result as shown in the Table 4. Therefore, addition of propylene oxide higher than 32% w/w can be considered uneconomical and HPK32 is selected as representative to study and understand the characteristics of HP-karaya. HPK32 is resynthesized in quantities (200 grams) sufficient for evaluation and to study its applicability in the design of controlled release formulations. Further characterization studies are performed on HPK32 only.

[0058] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, the method of preparation and characterization of hydroxypropyl karaya gum for controlled drug delivery applications is disclosed. The proposed method of preparation of modified or derivatized natural karaya gum aids in controlled or delayed or sustained or extended release drug delivery systems. The proposed method comprises a composition that is biodegradable, biocompatible, nontoxic, and eco-friendly.

[0059] The proposed method modifies the structure of the karaya gum, limiting uncontrolled hydration and forms a more porous gel structure. The proposed method provides a new natural and biodegradable polymer, making it safe for use in humans. The proposed method to modify karaya gum has the potential to be a commercially viable product. The proposed method improves the dispersability of the specific gum and reduces the rheological fluctuations.

[0060] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
, Claims:CLAIMS:
I / We Claim:
1. A method of preparation of hydroxypropyl karaya gum, comprising:
dissolving karaya gum in a solvent system to obtain a karaya gum mixture;
adding propylene oxide to the karaya gum mixture in the presence of at least one catalyst to form a reaction mixture;
stirring the reaction mixture at a temperature ranges between 30°C to 40°C for a time period of 2 to 6 hours;
neutralizing the reaction mixture with an acid that includes hydrochloric acid (HCl), hydrosulphuric acid (H2SO4), thereby precipitating the hydroxypropyl karaya gum with an organic solvent like methanol, or ethanol; and
separating the hydroxypropyl karaya gum from the reaction mixture.
2. The method as claimed in claim 1, wherein the propylene oxide is added to the karaya gum mixture under controlled conditions at a temperature varies between 30°C and 40°C and a reaction time varies between 2 hours and 6 hours.
3. The method as claimed in claim 1, wherein the catalyst includes sodium hydroxide or potassium hydroxide, which is at least 3% by weight of the reaction mixture.
4. The method as claimed in claim 1, wherein the solvent system comprises at least 75% by weight of the organic solvent isopropyl alcohol or ethanol or methanol and 25% by weight of water (v/v).
5. The method as claimed in claim 1, wherein the preparation of hydroxypropyl karaya gum (HP-karaya) from karaya gum is carried out using an etherification technique.
6. The method as claimed in claim 1, wherein the HP-karaya is prepared with different levels of hydroxypropylation, varies between HPK16 and HPK48, depending on different concentrations of the propylene oxide used for the preparation of the HP-karaya, wherein the propylene oxide concentration increases, causing an increase in the degree of hydroxypropylation in the HP-karaya.
7. The method as claimed in claim 1, wherein the propylene oxide concentration varies between 16% and 48% by weight, resulting in different degrees of hydroxypropylation in the HP-karaya, wherein the degrees of hydroxypropylation in the HP-karaya varies between 5% and 15% by weight of the HP-karaya.
8. The method as claimed in claim 1, wherein the hydroxypropyl karaya gum with 32% propylene oxide is safe and non-toxic at doses below 2000 mg/kg, wherein the HPK32 is clear of fungal and bacterial contamination including harmful bacteria, thereby indicating the safety and nontoxicity of lower percentage HP-karaya as well.
9. The method as claimed in claim 1, wherein the hydroxypropyl karaya gum exhibits sustained or controlled or extended or delayed drug release for at least 12 hours in acidic and alkaline conditions.