Claims:CLAIMS
We Claim:
1. A pharmaceutical composition comprising a bitter active pharmaceutical ingredient coated with cellulose polymer wherein the active pharmaceutical ingredient: polymer ratio is 70 to 98% w/w: 30 to 2% w/w and wherein the said composition is a taste masking pharmaceutical composition.

2. A pharmaceutical composition comprising a bitter active pharmaceutical ingredient coated with cellulose polymer wherein the active pharmaceutical ingredient: polymer ratio is 70 to 98% w/w: 30 to 2% w/w, viscosity of the said polymer is in the range of 5 to 50 cps and the ethoxy content of the said polymer is in the range of 45-50%.

3. The pharmaceutical composition of claims 1 or 2 wherein the said pharmaceutical composition is a directly compressible immediate release formulation.

4. The pharmaceutical composition comprising a bitter active pharmaceutical ingredient of claim 1 or 2 wherein the cellulose polymer is selected from the group consisting of ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, acetoxypropyl cellulose, ethyl acetyl cellulose.

5. The pharmaceutical composition comprising a bitter active pharmaceutical ingredient of claim 1 or 2 wherein the bitter active pharmaceutical ingredient is selected from the group consisting of aceclofenac, ampicillin, azithromycin, chlorpheniramine, cetrizine, clarithromycin, dextromethorphan, diclofenac, paracetamol, phenylbutazone, psuedoephedrine, ranitidine, spironolactone and theophylline.

6. A process of making taste masked composition comprising a bitter active pharmaceutical ingredient coated with cellulose polymer by microencapsulation or coacervation wherein the active pharmaceutical ingredient is coated with polymer using organic solvent and washed with a co-solvent.

7. The process of making taste masked composition of claim 6 wherein the said organic solvent is cyclohexane and the said co-solvent is non-polar solvent selected from the group consisting of n- hexane, mintroleum, petroleum ether and diethyl ether.

8. The process of making taste masked composition of claim 6 wherein the ratio of organic solvent to active pharmaceutical ingredient is 5:1.
9. A process of making a directly compressible taste masking composition with IR profile comprising the steps of:
(a) solubilizing cellulose polymer in organic solvent at a ratio of 2-30% of polymer to 98-70% of solvent and at a temperature of 70-78°C;
(b) coating core material of bitter API with the cellulose polymer of (a) by gradually lowering the temperature from 70 - 78°C to 30-35°C;
(c) optionally adding sweeteners to (b) and compress to obtain granules or tablet; and
wherein the said cellulose polymer has an ethoxy content of 45 - 50% and viscosity of 5 - 50 cps.
, Description:Direct compressible taste masking pharmaceutical composition
RELATED APPLICATION
This application is filed as a Complete Application with Indian Patent Office.
ABSTRACT
The present invention refers to a direct compressible (DC) taste masking pharmaceutical composition in the form of granules or its tablets of active pharmaceutical ingredients (APIs) of bitter taste using polymers. The taste-masking polymer is hydrophobic in nature and does not interfere with therapeutic activity of the API.
FIELD OF INVENTION
The present invention relates to taste masking of bitter APIs using polymer to obtain directly compressible (DC) pharmaceutical composition. The present composition is to obtain taste masked APIs in the form of granules or its tablets and to achieve immediate release (IR) dissolution profiles. The formulation described herein provides API: polymer ratios and the preparation method thereof.
DESCRIPTION OF THE RELATED ART
Oral route is most preferred route of administration of drugs, as itprovides convenient, low-cost of administration and often ensures dosing accuracy1. Many drugs possess bitter taste and therefore results in poor patient compliance especially in paediatric and geriatric population2-4. Taste masking of bitter drugscould provide a competitive advantage, especially in case of ‘over-the-counter’ formulations. Taste-masking of unpleasant and bitter drugs viz. aceclofenac, ampicillin, azithromycin, chlorpheniramine, cetrizine, clarithromycin, dextromethorphan, diclofenac, paracetamol, phenylbutazone, psuedoephedrine, ranitidine, spironolactone and theophylline, is desired for improved patient compliance for paediatrics and geriatric population.
Conventionally, sweeteners and flavoring agents have been used in taste-masking of bitter APIs. Many times, traditional methods and addition of sweeteners are not effective in masking the bitter flavor of highly bitter APIs such as paracetamol, clarithromycin and azithromycin.
The pharmaceutical and drug delivery companies are engaged in developing new innovative taste masking technologies to overcome the bitter taste of high volume consumed drugs.
Conventionally, cyclodextrin has been used for taste masking of APIs by forming a complex. Additionally, amongst many available taste-masking options, use of insoluble polymer coating to a drug has been the most cost effective and preferredoption3,4. In current approaches, typically taste masking technologies are based on nanohybrid systems5, hotmelt extrusion6, rupturing multiparticulates7, novel cyclodextrin compositions8 and so on. These processes offer numerous advantages over conventional approaches, as for instance, high drug loading in nano-lipidic particles9.
Applicability of all these techniques varies from drug-to-drug and their physicochemical traits including solubility in solvents and drug stability at varied temperatures. In addition, selection of appropriate taste masking process depends on various factors such as extent of drug bitterness, dose of drug, drug solubility, drug potency, ionic characteristics, micromeritics and dosage form to be developed.
Towards this, pharmaceutical technology is in quest to accelerate taste masking ability of either single or multiple drug(s) in a formulation to enhance patient compliance and reduction in manufacturing cost. Further, the resultant composition must achieve the desired drug release profile of the taste masked drug.

On the other hand, taste masking composition focus on exploring sweeteners of high intensity and natural origin, combining various approaches for synergistic effect and finding bitter taste masking agents which will compete with bitter drugs to bind with taste buds10.
Alternative approaches to mask the bitterness of certain APIs include, microencapsulation of active agent by achieving a consistent coating with the use of polymers, or cellulose polymers, for example ethyl cellulose (EC) and hydroxypropyl cellulose (HPC) or other cellulose derivatives. However, the use of said cellulose derivatives is quite often insufficient to provide adequate taste-masking of potently bitter active agents such as azithromycin and clarithromycin.
The following are the disadvantages of current taste masking processes:
1. Due to multiple components in a formulation, the timely release profile may vary;
2. Inability to control the delivery rate of API of the formulation.
3. Increased number of excipients increases the number of manufacturing processes which may affect both manufacturing time as well as cost.
Therefore, an optimized process of using polymers, suitable organic solvents and optimization of drug release profiles are challenges in taste masking process of drugs.

Summary of the Invention
The current invention addresses some of the critical aspects of producing taste masking formulations such as the selection of polymers with optimum viscosity, critical mole ratios (API:polymer) and chemical modifications of polymer including ethoxy content.
The present invention provides a taste masking composition of bitter active pharmaceutical ingredient (API) and hydrophobic polymer such as cellulose derivatives. The preferred cellulose derivative is ethyl cellulose.
In one aspect, the invention provides a taste masking composition with defined polymer viscosity and ethoxy content of polymer resulting in optimal taste masking of APIs that can be directly compressed (DC) as pharmaceutical granules or tablets for immediate release (IR) of a drug.
The invention also provides a process of making a directly compressible taste masking composition with IR profile comprising the steps of:
(a) solubilizing cellulose polymer in organic solvent at a ratio of 2-30% of polymer to 98-70% of solvent and at a temperature of 70-78°C;
(b) coating core material of bitter API with the cellulose polymer of (a) by gradually lowering the temperature from 70 - 78°C to 30-35°C;
(c) optionally adding sweeteners to (b) and compress to obtain granules or tablet; and
wherein the said cellulose polymer has an ethoxy content of 45 - 50% and viscosity of 5 - 50 cps.
BRIEF DESCRIPTION OF DRAWINGS
Figures 1a and 1b. Paracetamol DC granules
Figure 1a. UV spectra of free API- paracetamol and increased concentration with absorbance.
Figure 1b. Percentage cumulative drug release versus time in minutes: Dissolution profile of taste masked direct compressible immediate release (IR) of granules comprising paracetamol.
Figure 2. Clarithromycin DC granules
Percentage cumulative drug release versus time in minutes:
The average percentage dissolution of clarithromycin granules at pH 5 were computed from peak areas of HPLC, plotted as a function of dissolution time.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a direct compressible (DC) immediate release (IR) formulation for taste-masking comprising hydrophobic polymer and bitter APIs. Further, the present invention provides most efficient process driven taste masking formulation with cost-effective method of modulating IR release profile granules or its tablet as solid oral dosage forms.
In one aspect, the invention provides a taste masking API composition which can be directly compressed into tablets for achieving IR dissolution profiles.
In one embodiment, the present invention provides a taste masking composition comprising a bitter active pharmaceutical ingredient (API) using hydrophobic polymer such as cellulose derivatives. The preferred cellulose derivative is ethyl cellulose.
In one embodiment, the present invention provides suitable and pharmaceutically acceptable organic solvent(s) to dissolve the cellulose polymer(s) at specific temperature range of 70°C - 78°C and the process of coating the API by lowering the temperature and finally removal of organic solvent and yet maintaining the coating of polymer across the API. The organic solvents are selected from the group consisting of cyclohexane and hexane. More preferably, the organic solvent is cyclohexane. Further, co-solvents are utilized for washing of the granules. The co-solvents of the invention are non-polar solvents including but not limited to n-hexane, petroleum ether and diethyl ether.
The specific temperature as referred to herein wherein the organic solvent is used to dissolve the cellulose polymer is in the range of 70°C - 78°C. The preferred temperature to solubilize the ethyl cellulose polymer is 75°C. The temperature is then gradually lowered to 30 - 35°C at the time of coating the API. The change in the temperature is critical to the process of coating which results in achieving the immediate release dissolution profile alongside the taste masking composition.
Following this process, the coating of polymer is achieved on each API particle thus resulting in direct compressible granules and the process is commonly referred to as microencapsulation or coacervation.
Furthermore, polymer coating must essentially trigger the release of the active agent in a consistent manner to provide immediate release (IR) which the current taste masking composition achieves.
In one embodiment, the present invention provides a pharmaceutical process for obtaining the timely release profile using hydrophobic polymer and bitter API comprising the following steps:
a) Preparation of direct compressible granules using taste masking component as hydrophobic polymer viz. cellulose derivatives such as ethyl cellulose of defined viscosity and ethoxy content and bitter API, which imparts IR profile.
b) Further, above-mentioned composition of (a) is mixed with or without added sweeteners and may be compressed to obtain tablet.
It is generally preferred that the taste-masking component is a cellulose derivative, for example ethyl cellulose of defined viscosity and ethoxy content.
Taste masking of bitter APIs is achieved by forming a polymer coat around API particle. The said polymer coating on API particle is achieved by using ethyl cellulose of specific viscosity and ethoxy content.
The polymer is first solubilized in an organic solvent in a specific ratio, for example the ratios of polymer:solvent is 2-30% of polymer to 98-70% of solvent. More preferably the ratio of polymer: solvent is 5% of polymer : 95% of solvent. The organic solvent used to dissolve ethylcellulose polymer is preferably cycloehxane and its ratio with regard to API is preferably 5:1 (cyclohexane: organic solvent). Further, the ethyl cellulose coated API granules are washed with a co-solvent. The co-solvents used for washing include non-polar solvents selected from a group consisting of n-hexane, petroleum ether, diethyl ether and functionally similar non-polar solvents. More preferably, washing of API coated polymer is by using n-hexane.
Overall, the process of coating API with polymer using organic solvents is referred to as microencapsulation or co-acervation. It will be appreciated by a person skilled in the art that the use of polymer with specific ethoxy content and further using organic solvent in defined ratios is highly critical for the final formulation, especially, in achieving the immediate release of API according to pharmacopeial specifications.
The quantity of API used in the process herein, varies depending upon the potency and dosage requirements of particular API being utilized. In general, the quantity of said API ranges from about 70% w/w of the total weight of the composition to about 98% w/w of the total weight of the composition.
The amount of ethyl cellulose used in the formulation of the invention ranges from about 2% of the total weight of the composition to about 30% w/w of the total weight of the composition. More preferably, the API: Polymer ratio is in range of 93%: 7%. The amount of ethyl cellulose (or pharmaceutically acceptable cellulose derivatives) utilized depends upon the amount of the API used and upon the degree of bitterness of the said API.
It will, however, be appreciated by a person skilled in the art that the amount of cellulose derivative, that is, preferably ethyl cellulose of defined viscosity and ethoxy content will vary according to the amount of bitter pharmaceutical agent utilized and the degree of bitterness of said bitter API. The ethoxy content of polymer is in the range of 45-50% w/w. Preferably the ethoxy content in ethyl cellulose polymer is between 47-50% and more preferably the ethoxy content in ethyl cellulose polymer is 48.93% w/w. The pharmaceutical composition described above is sufficient to provide the taste-masking of a wide variety of bitter APIs, including potently bitter substances viz. paracetamol and clarithromycin.
In addition, cellulose derivatives used as taste masking component of the present invention is ethyl cellulose of defined viscosity and ethoxy content. The preferred defined viscosity is in the range of 5 to 50 cps. More preferably, the viscosity of the ethyl cellulose polymer is between 7 to 20cps and more preferably the viscosity of ethyl cellulose polymer 7cps. Other examples of suitable cellulose derivatives include, but are not limited to, methyl cellulose, hydroxyethyl cellulose, acetoxy propyl cellulose, ethyl acetyl cellulose. All of said cellulose derivatives of the present invention are readily available.
The invention also provides a process of making a directly compressible taste masking composition with IR profile comprising the steps of:
(a) solubilizing cellulose polymer in organic solvent at a ratio of 2 - 30% of polymer to 98 - 70% of solvent and at a temperature of 70 - 78°C;
(b) coating core material of bitter API with the cellulose polymer of (a) by gradually lowering the temperature from 70 - 78°C to 30-35°C;
(c) optionally adding sweeteners to (b) and compress to obtain granules or tablet; and
wherein the said cellulose polymer has an ethoxy content of 45 - 50% and viscosity of 5 - 50 cps.
The bitter APIs of the present invention include, but are not limited to, ampicillin, azithromycin, chlorpheniramine, cimetidine, clarithromycin, diphenhydramine, erythromycin, ibuprofen, paracetamol, penicillin, phenylbutazone, ranitidine, spironolactone, theophylline and any other API that has a bitter taste and is administered via oral route.
Administration of formulations of the present invention is achieved according to the normal oral mode of administration, which is in the form of DC granules or their tablets. Alternatively, the granules or tablets may be swallowed as a whole, if preferred, without chewing or admixing.
In addition, the direct compressible drug release profile of the present invention provides competitive unit production cost, eliminates heat and moisture, allows for prime particle dissociation, physical stability, and ensures particle size uniformity.
The following example illustrates the invention and its operability but is not to be construed as limiting the invention. It is emphasized that many variations of the disclosed invention are possible and is within the scope of the current invention.
Example 1.
Taste masked composition of bitter API viz. paracetamol and clarithromycin for timely release composition of the present invention was prepared by following process:
The required quantity of organic solvent (5 times w/v to API mass) cyclohexane was placed in a reaction vessel and was stirred with a speed of about 200 rpm and heated to 78°C. An adequate amount of ethyl cellulose (7%w/w) of preferred defined viscosity (7cps) and ethoxy content in the ethyl cellulose polymer of 48.93% w/w was used for preparing the taste masking composition. The polymer was dissolved in organic solvent cyclohexane by increasing the temperature from room temperature to 70-78°C over 10min and with stirring speed of 500rpm. Core material, bitter APIs (93%w/w) namely paracetamol or clarithromycin was added to the solution of heated cyclohexane. Stirring of the polymer solution and the drug suspended into it was continued for 1hr at 70-78°C. The preferred ratio of EC:API used was 7: 93. Thereafter, the temperature was gradually lowered to 30-35°C over 1hr and the polymer solution reverted into insoluble state forming a fine coat on the insoluble drug particles. The resultant polymer coated drug granules were allowed to sediment at room temperature. Excess cyclohexane was decanted and the granules were separated and washed with insoluble co-solvent n-hexane. Finally, taste masked granules were dried at 5°C.
Granules were compressed into tablets at appropriate compression weight using round, concave punches with desired hardness, disintegrating ability, and acceptable dissolution characteristics.
The direct compressible timely release granules were obtained and provide an unit dosage form having an IR dissolution profile as shown in Figure 1a (paracetamol) and Figure 2 (clarithromycin) for immediate release in acceptable degrees of hardness and resistance to chipping, as well as a short disintegration time.

Dissolution Parameters for paracetamol DC granules
Apparatus: 1 (Paddle); Medium: 900 ml of phosphate buffer pH 5.8; Speed & Time: 50 rpm and 30 minutes; Detector: UV 243 nm; Times: 10, 20, and 30 minutes.
Dissolution Parameters for Clarithromycin DC granules
Buffer solution: Prepare a solution containing 13.61 mg/ml of sodium acetate trihydrate in water. Prepare another solution by diluting 5.7 ml of glacial acetic acid to 1 L with water. Combine portions of the two solutions to obtain a pH of 5.0.
Medium: Buffer solution, 900 ml
Apparatus 2: 50 rpm, Time: 30 min
Tolerances: NLT 80% (Q) of the labelled amount ofC38H69NO13 is dissolved.
Example 2.
Dissolution for immediate release of drugs was studied by Indian Pharmacopoeia/United states Pharmacopoeia (I.P./ USP) method which comply their limits for respective timely release tablet using following parameters:
I. P. Dissolution method for Paracetamol (IR) tablet: (As shown in Figure 1b)
Medium: pH 5.8 phosphate buffer (6.8 g of monobasic potassium phosphate in 1000 ml of water; adjust with 0.2 N sodium hydroxide to a pH of 6.8 ± 0.1); 900 ml;
Apparatus1: 50 rpm for tablets labelled to contain 125 mg of paracetamol.
Times: 30 minutes, Detector: UV 243 nm.
Withdraw a suitable volume of the medium and filter and dilute a suitable volume of the filtrate with the same solvent. Measure the absorbance of the resulting solution at the maximum at about 243 nm. Similarly measure the absorbance of a solution of known concentration of paracetamol RS. Calculate the content of C8H9NO2.
Tolerances: Not less than 80 per cent of the stated amount of C8H9NO2
Figure 1b provides the result of the dissolution profile of taste masked direct compressible immediate release (IR) of granules comprising paracetamol as described above.

Dated 30th March 2018
Kausalya Santhanam
(Agent for the Applicant)
PA/IN/1183

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