FORMULATION COMPRISING GEFITINIB AS ORAL SUSPENSION

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions of gefitinib and process of preparation thereof.

BACKGROUND OF THE INVENTION

Gefitinib is an antineoplastic agent and it is chemically designated as 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin) propoxy] with molecular formula C22H24CIFN4O3 and currently indicated for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Gefitinib is a useful addition to treatment of patients with locally advanced head and neck cancer.

Gefitinib is commercially available as film coated tablets of 250 mg strength under the trade name of Iressa® manufactured by Astrazeneca.

Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells.

Gefitinib is slowly absorbed after oral administration with peak plasma levels occurring 3-7 hours after dosing. It was also reported that mean oral bioavailability is 60%. Biotransformation of gefitinib is via hepatic metabolism and cytochrome P450 enzymes (especially CYP3A4).

Gefitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1400 L following intravenous administration. In vitro binding of gefitinib to human plasma proteins (serum albumin and a 1-acid glycoprotein) is 90% and is independent of drug concentrations.

Gefitinib is cleared primarily by the liver, with total plasma clearance and elimination half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration. Excretion is predominantly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.

Daily oral administration of gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are achieved within 10 days.

U.S. Patent nos. 5457105, 5616582, 5770599 discloses synthesis of gefitinib and pharmaceutically acceptable salts. The ingredients for formulation of conventional tablets detailed in this prior art comprise active ingredient, lactose, croscarmellose sodium, maize starch, polyvinyl pyrrolidone, magnesium stearate. In addition, EP 0823900 Bl and WO 96/33980 disclose the same.

WO 2005/070909, WO 2010/076810 and U.S. Patent application no. 20100137586 discloses process for preparation of gefitinib.

WO 2006/090413 describes a stable novel crystalline form of gefitinib and a process for the preparation of the same which is useful in the treatment of a variety of solid tumors.

The prior art discloses methods and pharmaceutical composition of a therapeutic agent which enhances sensitivity of a cancer to a molecular target drug in U.S. Patent application no. 20120064090, U.S. Patent no. 8017321 corresponding PCT application no. PCT/US2005/002325. In addition U.S. Patent application no. like 20110294686, 20070270505 also disclose the same.

U.S. Patent application no. 20090098138 corresponding PCT application no. PCT/US07/66857 and U.S. Patent application no. 20100173285 discloses a method of detecting the expression of a protein from circulating cancer cells and EGFR mutations to determine patient responsiveness to gefitinib administration.

U.S. Patent application no. 20090185999 and 20090186892 discloses quinazoline derivatives for treating lung cancers.

Gefitinib is presently available as tablet dosage form in market. None of the above said prior arts discloses and/or envisages an oral suspension. Hence, the development of an oral suspension alleviates problems associated with swallowing tablets in head and neck cancer patients. The oral suspension dosage form can also be a viable alternative for geriatric patients who unable to or prefer not to swallow a solid dosage form since it offers improved patient compliance and is stable with good organoleptic properties.

Since gefitinib is having all the above favorable features suitable to formulate an oral suspension, the work on present invention was taken up.

The present invention, relates to design and development of an oral suspension containing gefitinib and a process for its preparation, indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.

There is a need to work on formulations and process thereof, which proves better therapeutic efficacy, ease of oral administration and to be economical for large-scale production.

OBJECTIVES OF THE INVENTION

Accordingly, the main objective of the present invention is to design and develop an oral suspension containing gefitinib for monotherapy treatment for locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.

Another objective of this invention is to provide a dosage form ensuring adequate therapeutic levels of drug concentration.

Another objective of the present invention is to provide a stable oral liquid composition.

Another objective of the present invention is to provide an oral liquid formulation with a palatable taste.

Another objective of this invention is to provide a desirable oral formulation for the treatment of elderly patients to swallow easily.

Yet another objective of the present invention is to provide simple process for the preparation of a stable aqueous formulation of gefitinib.

Yet another objective of the present invention enhances patient compliance.

Accordingly, further objective of this invention is to provide the pharmaceutical composition of an oral suspension to ensure adequate therapeutic levels for the therapy against aforementioned diseases.

Accordingly, further objective of this invention is to meet the particular needs of patients who find difficulty in swallowing solid oral dosage forms.

More especially, the objective of the present invention is to develop a process for preparing the oral suspension comprising active ingredient, one or more of a vehicle, suspending agent, preservatives, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and the like.

STATEMENT OF INVENTION

Accordingly, the main embodiment of the present invention is to design and develop a stable aqueous oral formulation that can be swallowed easily and comprising gefitinib, a process for its preparation, wherein the said formulation has pH in the range of about 2.5 to 5.5 for the monotherapy treatment of locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.

DETAILED DESCRIPTION OF THE INVENTION

An aqueous suspension for oral administration in humans comprising of therapeutically effective amount of gefitinib, one or more of a vehicle, suspending agent, preservatives, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and the like intended to treat metastatic non-small cell lung cancer or unresectable head and neck cancer.

The formulation of the present invention comprises wherein the oral suspension contains a therapeutically effective pharmaceutical ingredient, gefitinib used in the range of about 0.1% to about 20%, by weight by volume of the total suspension.

Compositions of the present invention include a vehicle which is pharmaceutically acceptable serves as the external phase of the suspensions. A preferred vehicle of the present invention may include water, glycerin, propylene glycol and mixtures thereof.

Optionally other vehicles may include but not restricted to, sorbitol solution, polyethylene glycol and the like.

The vehicle used either single or in combinations in the range of about 1% to about 90%, by weight by volume of the total suspension.

The formulation of the present invention may include an appropriate amount of suspending agents that can add a desired viscosity and flow to a formulation or effective to stabilize the pharmaceutically active agent within the aqueous composition. For example, in a suspension a viscosity enhancer will help to keep the active ingredient suspended to allow accurate dosing. A preferred suspending agent of the present invention may include hypromellose, polyvinylpyrrolidone, magnesium aluminium silicate and xanthan gum.

Optionally other suspending agents may include but not restricted to, carbomer, hydrocolloid gums like guar gum, gum tragacanth and cellulose derivatives for example methyl-, ethyl- and propyl celluloses; hydroxyalkyl-celluloses, hydroxyl propyl celluloses, hydroxylpropylalkyl celluloses, sodium carboxy methyl cellulose, micro crystalline cellulose and the like including dextrans, dextrins, cyclodextrin, polyvinyl resins, polyethylene glycol, polyethylene oxide, sodium alginate and the like.

The suspending agents used either single or in combinations in the range of about 0.05% to about 20%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of preservatives to prevent growth of micro organisms. A preferred anti microbial agents of the present invention is benzyl alcohol, methyl and propyl parabens.

Optionally other preservatives may include but not restricted to, butyl paraben, ethyl paraben, sorbic acid, potassium sorbate, benzalkonium chloride, benzoic acid and its derivatives such as sodium benzoate and the like.

The preservatives used either single or in combinations in the range of about 0.005% to about 5%, by weight by volume of the total suspension.

Compositions of the present invention include wetting agents to increase suspendability of hydrophobic drugs in aqueous media by reducing interfacial tension between drug particles and the suspension vehicle, thereby allowing penetration of suspension vehicle into drug aggregates and/or drug particle pores. A preferred wetting agent of the present invention may include sodium lauryl sulphate and polyoxyethylene derivatives of sorbitan esters (polysorbate 20,40, 60 and 80).

Optionally other wetting agents may include but are not restricted to, poloxamers (ethylene oxide propylene oxide block copolymers) of different HLBs, polyethylene glycols and the like.

The wetting agents used either single or in combinations in the range of about 0.05% to about 20%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of sweetening agents used for better patient acceptability of the dosage form and also enhances the flavor system. A preferred sweetening agent of the present invention may include sucralose, sorbitol solution and saccharin.

Optionally other sweetening agents may include but not restricted to, natural sweeteners such as sugars eg. fructose, sucrose, glucose, sugar alcohols such as mannitol or mixtures thereof and artificial sweeteners such as sodium saccharin, potassium saccharin, sodium cyclamate, aspartame, thaumatin, acesulfame potassium, altitame, neotame, xylose, ribose, mannose, galactose, neohesperidin dihydrochalcone and the like.

The sweetening agent used either single or in combinations in the range of about 0.01% to about 40%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of buffering agents to adjust / maintain the pH of suspension. The suspension according to present invention has a pH of about 2.5 to 5.5. A preferred buffering agent of the present invention is selected from citric acid, sodium citrate or mixture thereof.

Optionally other agents include but not restricted to, phosphoric acid, succinic acid, tartaric, lactic acid, acetic acid and salts thereof, sodium hydroxide, sodium phosphate, sodium chloride, disodium hydrogen phosphate, sodium hydrogen carbonate, monosodium phosphate, monopotassium phosphate, potassium citrate and mixtures thereof.

The buffering agents used either single or in combinations to adjust pH (2.5 to 5.5) in the range of about 0.01% to about 10%, by weight by volume of the total suspension.

Compositions of the present invention include anticaking agent to prevent the formation of cake in formulation of suspension. A preferred anticaking agent of the present invention may include colloidal silicon dioxide.

Optionally other anticaking agent may include but not restricted to, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate and the like.

The anticaking agent used either single or in combinations in the range of about 0.01% to about 10%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of chelating agents in a suitable concentration range to stabilize the product during storage. A preferred chelating agent of the present invention may include disodium edetate and the like. Optionally other agents may include but not restricted to, edetic acid, tartaric acid, malic acid, citric acid and salts thereof.

The chelating agent used either single or in combinations in the range of about 0.01% to about 5%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of antioxidants in a suitable concentration range to prevent oxidation. A preferred antioxidant of the present invention may include sodium metabisulfite.

Optionally other agents include but not restricted to, ascorbic acid, sodium sulfite, sodium bisulfate, sodium thiosulfate, sodium ascorbate, sodium formaldehydesulfoxylate, malic acid, alkyl gallates like propyl gallate, lauryl gallate, or octyl gallate and the like.

The antioxidant used either single or in combinations in the range of about 0.01% to about 5%, by weight by volume of the total suspension.

Compositions of the present invention comprise pharmaceutically acceptable aqueous or oil based flavoring agents to impart a pleasant flavor and often odor to a pharmaceutical preparation and can enhance patient compliance by making the composition more palatable. A preferred flavoring agent of the present invention is lemon flavor.

Optionally, non-limiting examples of flavoring agents may include but not restricted to orange sweet oil, spearmint oil, citronella oil, black pepper oil, pine apple, cherry, vanilla, honey, lemon, strawberry, raspberry, black current, caramel chocolate, mint cool, fantasy flavor, bubble gum, citrus, lemon, lime, apple, apricot, peppermint, spearmint peach, pear, plum flavor and the like.

The flavoring agent used either single or in combinations in the range of about 0.05% to about 10%, by weight by volume of the total suspension.

Compositions of the present invention may include an appropriate amount of pharmaceutically acceptable aqueous or oil based colors to provide a product with a more aesthetic and/or distinctive appearance. A preferred coloring agent of the present invention is D&C Yellow No. 10.

Optionally other agents includes natural or synthetic dyes but not restricted to carmoisine, FD&C Yellow No.5, FD&C Yellow No.6, FD&C Red No.3, FD&C Red No.20, FD&C Blue No.2, D&C Green No.5, , D&C Yellow No.7, D&C Orange No.5, D&C Red No.8, caramel and the like.

The coloring agents used either single or in combinations in the range of about 0.001% to about 2%, by weight by volume of the total suspension.

An aqueous suspension may further include one or more pharmaceutically acceptable additives.

The particle size of the present invention is measured using light scattering technique (Malvern Sizer). The fine particle size contributes to homogeneity on prolonged storage, reduced grittiness, and may enhance bioavailability in the case of poorly soluble drugs.

The average particle size of the gefitinib in the present invention is less than about 50 urn.

The present invention containing pharmaceutical active agent present at concentrations of 50 mg per mL, 25 mg per mL may be prepared with the above mentioned excipients using different proportions.

An aqueous suspension of the present invention is easily administrable for geriatric patients and thus patient compliance can be achieved.

A pharmaceutical composition of the present invention may be used in the treatment of the human or animal body by therapy.

A process for the preparation of an oral suspension comprising mixing therapeutically effective amount of Gefitinib with vehicle containing preservatives followed by addition of one or more suspending agent dispersed in water, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent and coloring agents where in the said suspension has a pH from 2.5 to 5.5.

The formulations of the present invention were found to be stable throughout the stability testing storage period.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are to be embraced within their scope. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the rationale and scope of the invention.

Figure 1 shows the bioavailability study of the formulation of the present invention and tablet dosage form of gefitinib.

The details of the process of the invention are provided in the examples given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. The preparation of the present invention that can be administered by the oral route is carried out according to the following process:

EXAMPLES

The components illustrated by the examples 1 to 20 are expressed in % by weight based on each composition.

In a specific embodiment the present invention provides a process for preparation of a composition, which comprises intimately mixing gefitinib with a vehicle containing preservatives followed by addition of one or more suspending agent dispersed in water, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and mixed properly through high speed homogenizer until a homogeneous suspension is obtained or as mentioned under individual examples.

The compositions of Example 1 to 20, contains the

Table 1

The processing steps involved in manufacturing an oral suspension given in example 1 to 4 were given below:

1. Suspending agent was dispersed in water under stirring.

2. Preservative was added to vehicle under stirring followed by addition of wetting agent and added to step (1)

3. pH of the suspension was adjusted to a desired value as needed by adding buffering agents and added to step (2).

4. Sweetening agent was added to step (3) under stirring.

5. Anticaking agent was added to step (4) under stirring

6. Pharmaceutical active agent was added to step (5) under stirring.

7. Antioxidant was added to step (6) under stirring.

8. Flavor was added to step (7) under stirring.

9. Finally the volume was adjusted with water.

Table 2

The formulations given in examples 5 to 8 were prepared using similar procedure described in example 1 to 4. Preservatives like methyl paraben and propyl paraben were heated in glycerol in example 5 and 6.

The formulations given in examples 9 to 12 were prepared using similar procedure described in example 1 to 4.

The formulations given in examples 13 to 16 were prepared using similar procedure described in example 1 to 4. FD&C Yellow No.5 was used as coloring agent in examples 14,15 and 16 respectively.

Table 5

The formulations given in examples 17 to 20 were prepared using similar procedure described in example 1 to 4. Disodium edetate was used as chelating agent, D&C Yellow No. 10, FD&C Yellow No.6, FD&C yellow No.5 and carmoisine were used as coloring agents in examples 17,18,19 and 20 respectively.

BIOAVAILABILITY STUDY FOR THE COMPOSITIONS IN ACCORDANCE WITH THE INVENTION:

The plasma kinetics of the oral suspension as described in above mentioned examples have been compared with those of the gefitinib tablets in a comparative study. This comparative study was carried out with wistar albino rats; weighing 150-280 grams which were divided into different sets of study (one male and one female in each set) and fasted overnight prior to dosing, but were permitted water ad libitum. Both formulations were administered at the dose of 20 mg/kg body weight. Blood samples were collected by puncturing retero-orbital sinus of the anaesthetized rats (with anesthetic light isoflurane) at different intervals post administration. Blood collection was done in prefilled heparin centrifugation tubes.

The blood samples collected were subjected for the subsequent centrifugation and followed by analytical procedure with the use of LCMS technique. The areas under the blood drug concentration versus time curves were calculated by the trapezoidal rule. The analysis was done with respect to AUC (area under curve) and Cmax (maximum concentration).

The average AUC and Cmax values from typical trial runs are shown in the following table.

Table 6

As will be seen from the above table, compositions in accordance with the present invention exhibit adequate bioavailability (AUC and Cmax) in comparison with the commercial tablet dosage form.

The aforementioned table gives an account of the bioavailability (AUC, Cmax) of the Gefitinib tablet dosage form and formulation in the present invention.

ADVANTAGES OF THE INVENTION

a) Oral suspension of an aniloquinazoline derivative for example gefitnib is prepared which is used as EGFR tyrosine kinase inhibitor for the monotherapy for the continued treatment of patients with locally advanced or metastatic non-small cell lung cancer or unresectable head and neck cancer.

b) Patient compliance can be achieved in the present invention as it is easy to be administered so particularly preferable in geriatric patients.

c) Gefitinib oral suspension can be a viable alternative to patients who find it difficult to swallow solid dosage forms.

d) The advantage also lies in the attainment of adequate therapeutic levels of drug concentration in comparison with the commercial tablet dosage form.

e) The advantage further encompasses the stability aspects and the formulation is found to be stable throughout the period of the stability study.

f) Industrial applicability, as ease of manufacturing procedure for the scale-up batches and more economical.

g) Particularly till date, the use of this said composition in an orally administrable suspension is not commercially available.

We Claim:

1. An oral suspension comprising gefitinib along with one or more pharmaceutically acceptable additives.

2. The oral suspension of claim 1, wherein the average particle size of the gefitinib is less than about 50 um.

3. The oral aqueous suspension of claim 1, wherein the pharmaceutically acceptable additives comprise one or more of a vehicle, suspending agents, preservatives, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent, coloring agents and the like.

4. The oral aqueous suspension according to claim 3, wherein the vehicle is selected from water, glycerin, propylene glycol or mixtures thereof.

5. The oral aqueous suspension according to claim 3, wherein the suspending agent is selected from hypromellose, polyvinylpyrrolidone, magnesium aluminium silicate, xanthan gum and carbomer or mixtures thereof.

6. The oral aqueous suspension according to claim 3, wherein the preservative is selected from methyl paraben, propyl paraben or salts or benzoic acid or sodium benzoate thereof, either individually or in combination.

7. The oral aqueous suspension according to claim 3, wherein the wetting agent is selected from polyoxyethylene sorbitan esters such as polysorbate 20, 80, sodium lauryl sulphate, poloxamers, polyethylene glycol or mixtures thereof.

8. The oral aqueous suspension according to claim 3, wherein the sweetening agent is selected from sucralose, sorbitol solution and saccharin.

9. The oral aqueous suspension according to claim 3, wherein the buffering agent is selected from citric acid, sodium citrate or mixture thereof to adjust the pH of the suspension from 2.5 to 5.5.

10. The oral aqueous suspension of claim3, wherein the anticaking agent is selected from colloidal silicon dioxide, calcium phosphate tribasic or mixtures thereof.

11. The oral aqueous suspension according to claim 3, wherein the antioxidant is selected from sodium metabisulfite, propyl gallate or ascorbic acid.

12. A process for producing an aqueous oral suspension according to any one of preceding claims, which comprises mixing therapeutically effective amount of Gefitinib with vehicle containing preservatives followed by addition of one or more suspending agent dispersed in water, wetting agents, sweetening agents, buffering agents, anticaking agents, chelating agent, antioxidants, flavoring agent and coloring agents.