STABLE ORAL COMPOSITION OF CYCLOPHOSPHAMIDE

Abstract

The present invention relates to a stable oral composition of cyclophosphamide or a pharmaceutically acceptable salt thereof. Said cyclophosphamide composition may be in the form of a powder for oral solution, which may provide improved stability, ease of reconstitution, and better palatability suitable for pediatric patients. Furthermore, the invention relates to a process for preparing said cyclophosphamide powder for oral solution.

Description

This application relates to India's provisional application no. sIN201921027551, filed on July 10, 2019, and is incorporated herein in its entirety. FIELD OF INVENTION The present invention relates to an oral stable cyclophosphamide composition. This cyclophosphamide composition may be in the form of a powder for oral solution, which may provide improved stability, ease of reconstitution, and better palatability suitable for pediatric patients. Furthermore, the invention relates to a process for preparing said cyclophosphamide powder for oral solution. In addition, the invention relates to a kit comprising said oral stable cyclophosphamide composition. BACKGROUND OF THE INVENTION Cyclophosphamide, chemically known as (RS)-N,N-bis(2-chloroethyl)1,3,2-oxazaphosphine-2-amine 2-oxide, is a synthetic antineoplastic drug used in the treatment of malignancies and nephrotic syndrome. Malignant conditions include lymphomas, multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and breast carcinoma. Currently, three pharmaceutical forms of cyclophosphamide are available on the market: tablets, capsules, and lyophilized powder for solution by injection, specifically CYTOXAN®. The previously available lyophilized powder contained cyclophosphamide monohydrate and mannitol; however, this product is no longer marketed. Additionally, cyclophosphamide monohydrate is available in pure form, without any thickener. However, this product is difficult to dissolve and, therefore, difficult to reconstitute. US patent no. 4537883 discloses a lyophilized pharmaceutical solid composition containing cyclophosphamide for reconstitution with water to provide a solution for oral or parenteral administration. Patent application EP n.sEP2745833 A1 discloses a dispersible or orodispersible cyclophosphamide tablet that can be administered orally after being dispersed in an aqueous solution or beverage, such as water. Patent application EP n.sEP3139929 A4 discloses a ready-to-dilute or ready-to-use cyclophosphamide-containing composition comprising ethanol and an acidifying agent, such as citric acid. Patent EP n.sEP0271622 B1 discloses a lyophilized composition of cyclophosphamide with galactitol. US patent no. 2US5036060 discloses a mannitol-free cyclophosphamide lyophilized composition with sodium chloride. US patent no. 5418223 discloses a process for the preparation of a lyophilized cyclophosphamide composition. PCT application no. sWO2014068585 discloses a composition comprising lyophilized cyclophosphamide monohydrate and its preparation process. Currently marketed formulations are suitable for adults but are not approved for pediatric patients. Children often have difficulty swallowing tablets, and intravenous administration is quite traumatic. This is particularly dangerous for newborns and young children. Furthermore, intravenous chemotherapy is not suitable for outpatient treatment, as children must take a daily dose for months. Therefore, cyclophosphamide is generally administered to children using the powder for IV formulations. However, cyclophosphamide powder dissolves slowly in water, resulting in a cloudy suspension rather than a true solution. Consequently, ensuring the correct oral dosage for pediatric patients is challenging. Furthermore, the lyophilization method requires sophisticated equipment and skilled personnel; therefore, the cost of the lyophilized powder and the product's stability are additional limiting factors in preparing a suitable powder for the oral solution formulation appropriate for pediatric patients. Furthermore, once cyclophosphamide is dissolved in solution, it must be administered immediately (i.e., within 48 hours), as cyclophosphamide is not stable long-term in aqueous solution. Therefore, oral administration of cyclophosphamide using dissolved powder is always performed under strict hospital supervision, requiring the child to visit the hospital for frequent doses over several months. Therefore, there is an urgent need to provide a new pharmaceutical form of cyclophosphamide that can facilitate effective administration, particularly for children. The inventors of the present invention have developed a stable powder for oral solution comprising a mixture of cyclophosphamide and mannitol, which can be reconstituted with a diluent (e.g., water) within a kit (e.g., a dual-chamber bottle) prior to administration. Furthermore, the stable powder for oral solution comprises cyclophosphamide, mannitol, and optionally a sweetener, flavoring agent, and / or preservative, wherein the powder for oral solution is prepared without lyophilization. Therefore, the powder for oral solution provides ease of reconstitution, improved stability, and good palatability, making it suitable for the treatment of malignant neoplasms and nephrotic syndrome in pediatric patients. OBJECTS OF THE INVENTION The main object of the present invention is to provide a stable oral composition comprising cyclophosphamide and one or more pharmaceutically acceptable excipients, wherein said composition is in the form of a powder for oral solution. Another object of the present invention is to provide a stable powder for oral solution comprising a mixture of cyclophosphamide and one or more pharmaceutically acceptable excipients, wherein said powder is not obtained by lyophilization. Another object of the present invention is to provide a stable powder for oral solution comprising a mixture of cyclophosphamide and mannitol, wherein the mannitol-cyclophosphamide ratio is not greater than approximately 1.2:1 and optionally consisting of sweetener, flavoring agent and / or preservative, wherein said powder is not obtained by freeze-drying. Another object of the present invention is to provide an oral composition comprising: (a) a powder mixture of cyclophosphamide and mannitol, (b) a diluent, wherein said powder can be reconstituted with diluent prior to administration. Another object of the present invention is to provide an oral composition comprising: (a) a powder mixture of cyclophosphamide and mannitol, (b) a diluent and optionally consisting of sweetener and flavoring agent, wherein the powder can be reconstituted with diluent prior to administration. Another object of the present invention is to provide an oral composition comprising: (a) a powder mixture of cyclophosphamide and mannitol, (b) a diluent and optionally consisting of a sweetener, flavoring agent and / or preservative, wherein the powder can be reconstituted with diluent prior to administration. Another object of the present invention is to provide an oral composition comprising: (a) a powder mixture of cyclophosphamide, mannitol and optionally consisting of sweetener and flavoring agent and (b) a diluent, wherein the powder can be reconstituted with diluent prior to administration. Another object of the present invention is to provide an oral composition comprising: (a) a powder mixture of cyclophosphamide, mannitol and optionally consisting of a sweetener, flavoring agent and / or preservative and (b) a diluent, wherein the powder can be reconstituted with diluent prior to administration. Another object of the present invention is to provide a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide and mannitol and (b) a diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. Another object of the present invention is to provide a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide, mannitol and optionally consisting of sweetener, flavoring agent and / or preservative, (b) a diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. Another object of the present invention is to provide a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide and mannitol, (b) a diluent, optionally comprising sweetener, flavoring agent and / or preservative, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. Another object of the present invention is to provide a process for the preparation of a stable powder for oral solution comprising cyclophosphamide and one or more pharmaceutically acceptable excipients. Another object of the present invention is to provide a process for the preparation of stable powder for oral solution comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture into a conditioning container. Another object of the present invention relates to a process for preparing a kit comprising a stable powder for oral solution and a diluent comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture and water as a diluent into a kit. Another object of the present invention is to provide a method for the treatment of malignant neoplasms in a pediatric patient comprising administering an oral composition from a kit comprising: (a) the powder for oral solution comprising a mixture of cyclophosphamide and mannitol, (b) diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. BRIEF DESCRIPTION OF THE INVENTION In a first embodiment, the present invention consists of providing a stable oral composition comprising cyclophosphamide and one or more pharmaceutically acceptable excipients, wherein said composition is in the form of a powder for oral solution. In another embodiment, the present invention relates to a stable powder for oral solution frAznnn / zznz / E / YiAi stable powder for oral solution comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture into a conditioning container. In another embodiment, the present invention relates to a process for preparing a kit comprising a stable powder for oral solution and a diluent comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture and water as a diluent into a kit. In another embodiment, the present invention relates to a method for treating malignant neoplasms in a pediatric patient comprising administering an oral composition from a kit comprising: (a) the powder for oral solution comprising a mixture of cyclophosphamide and mannitol, (b) diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. DETAILED DESCRIPTION OF THE INVENTION The detailed descriptions and examples provided herein are illustrative, and any modifications or variations within the scope of the invention will be obvious to a person skilled in the art. Furthermore, unless otherwise defined, all technical and scientific terms and expressions used herein shall have the meaning understood by a person skilled in the art. In one aspect, the present invention provides a stable oral composition comprising cyclophosphamide in the form of a powder for solution that can be reconstituted with a diluent (e.g., water) prior to administration to a patient. The term cyclophosphamide, as used within the descriptive memory, refers to the drug cyclophosphamide and its pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, and pharmaceutically acceptable prodrugs thereof. Without being tied to any theory, the term "stable," as used throughout this specification, refers to cyclophosphamide powder for oral solution, wherein said powder contains no more than 5% w / w of total cyclophosphamide impurity. Preferably, the impurity is no greater than 3.5%, and more preferably, the impurity is no greater than 2% of cyclophosphamide. In another embodiment, "stable powder for oral solution" refers to a pharmaceutical composition in which the active ingredient, cyclophosphamide, is present in an amount of at least 90% of the amount specified on the original label for each of such ingredient under the specified storage conditions (i.e., at least three months at 40°C / 75% RH, 30°C / 65% RH, and 25°C / 60% RH).In a preferred embodiment, the oral pharmaceutical composition of the present invention is a powder for oral solution comprising a mixture of cyclophosphamide and mannitol, wherein said powder is not obtained by lyophilization. Said powder for oral solution does not give rise to the formation of a significant amount of impurities when stored under specified storage conditions. The expression "specific storage conditions," as used throughout this specification, refers to the pharmaceutical composition of the present invention stored for at least three months at 40°C / 75% RH, 30°C / 65% RH, and 25°C / 60% RH. The term "cyclophosphamide impurities," as used throughout this specification, refers to any identified or unidentified degradation product or structurally related impurity to cyclophosphamide that will arise from the manufacturing process or during storage. The term diluent, as used throughout this specification, refers to a suitable solvent in which cyclophosphamide can be dissolved. In a preferred embodiment, the diluent for the present invention is water. The term "kit," as used throughout this specification, refers to the packaging container comprising two components. In one embodiment, a kit comprises a two-component container comprising: (a) a powder mixture of cyclophosphamide and mannitol in the first component, and (b) a diluent in the second component. In another embodiment, the kit may comprise a dual-chamber container comprising: (a) the powder mixture of cyclophosphamide and mannitol, and (b) a diluent, wherein the powder can be reconstituted with the diluent in the kit prior to administration. In a preferred embodiment, a kit comprises a dual-chamber bottle comprising: (a) the powder mixture of cyclophosphamide and mannitol, (b) water, optionally comprising sweetener, flavoring agent and / or preservative, wherein said powder can be reconstituted with water in said kit prior to administration. The use of bottles of varying shapes, sizes, and mechanisms for reconstituting the powder mixture with the diluent falls within the scope of the present invention. Furthermore, other similar packaging containers may also be used to allow the reconstitution of the powder mixture with a diluent and the administration of the oral solution to a patient. The present invention is not limited to a double-chamber bottle, and equivalent packaging containers are included within the scope of the invention. In another embodiment, the amount of cyclophosphamide in said stable powder for oral solution frAznnn / zznz / E / YiAi is in the range of 5 mg / ml to 50 mg / ml, more preferably from 10 mg / ml to 30 mg / ml. Furthermore, the stable oral composition of the present invention comprises one or more pharmaceutically acceptable excipients selected from the group consisting of lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose, and maltodextrin, or a mixture thereof. In a preferred embodiment, the excipient is mannitol. Moreover, the amount of mannitol is selected such that the mannitol-cyclophosphamide ratio is no greater than approximately 1.2:1 in the powder for oral solution. Additionally, the oral pharmaceutical composition of the present invention may also comprise at least one sweetener, at least one flavoring agent, and / or at least one or more preservatives. These excipients may be added to the powder mixture or dissolved in the diluent. The sweetener may be selected from the group consisting of alitame, acesulfame potassium, aspartame, D-tryptophan, dextrose, erythritol, fructose, galactose, glycerol, glycyrrhizin, glucose, isomaltitol, xylitol, xylose, lactitol, lactose, levulose, maltitol, maltodextrin, maltol, maltose, mannitol, corn syrup, neohesperidin dihydrochalcone, neotame, saccharin, silclamate, sorbitol, sucralose, sucrose, tagatose, thaumatin, and trehalose. Preferably, the sweetener used in the stable oral composition of cyclophosphamide is sucralose. Preferably, the ratio of cyclophosphamide to sweetener is in the range of 50:0.1 to 50:2, more preferably the ratio of cyclophosphamide to sweetener is 50:1. The ratio of cyclophosphamide to sweetener in the oral composition may be varied depending on the type of sweetener. The flavoring agent may be selected from the group consisting of essential oils, including peppermint oil, orange oil, and lemon oil, or from fruit flavorings. Preferably, the flavoring agent used in the stable oral composition of cyclophosphamide is a berry flavoring. Preferably, the ratio of cyclophosphamide to flavoring agent is in the range of 50:0.01 to 50:1, more preferably 50:0.2. The ratio of cyclophosphamide to flavoring agent in the oral composition may be varied depending on the type of flavoring agent. Preservatives may be selected from the group consisting of alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylene glycol, butylparaben, calcium acetate, calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, glycerin, hexetidine, imidurea, monothioglycerol, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, propionic acid, propylene glycol, methylparaben, propylparaben, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfur dioxide and thimerosal.Preferably, the preservatives used in the stable oral composition of cyclophosphamide are methylparaben and propylparaben. Preferably, the ratio of cyclophosphamide to preservative is in the range of 50:0.5 to 50:5, more preferably the ratio of cyclophosphamide to flavoring agent is 50:2.33. The ratio of cyclophosphamide to preservative in the oral composition may vary depending on the type of preservative. In another embodiment, the compositions of the present invention can be used for single-dose or multiple-dose administration to adults as well as to pediatric patients. The stable powder for oral solution is reconstituted with the diluent to obtain the reconstituted solution. This solution can be administered as a single dose for one-time use only or as multiple doses for multiple administrations. The reconstituted solution in a dual-chamber bottle remains stable for at least 48 hours after storage at 25°C / 60% RH and for at least 14 days after storage at 2–8°C. In another embodiment, the stable powder for oral solution comprises a mixture of cyclophosphamide and mannitol, wherein the mannitol:cyclophosphamide ratio is no greater than approximately 1.2:1 and optionally consists of a sweetener, flavoring agent, and / or preservative, wherein said powder is not obtained by lyophilization. The mannitol can function as a cyclophosphamide stabilizer in said stable powder for oral solution. The mannitol can also act as a sweetener for said oral composition of the present invention. In a preferred embodiment, the mannitol:cyclophosphamide ratio is approximately 1:1. In another embodiment, the present invention relates to an oral composition comprising: (a) a powder mixture of cyclophosphamide and mannitol, (b) a diluent and optionally consisting of a sweetener, flavoring agent and / or preservative, wherein the powder can be reconstituted with diluent prior to administration. In another embodiment, the present invention relates to an oral composition comprising: (a) a powder mixture of cyclophosphamide, mannitol and optionally consisting of a sweetener, flavoring agent and / or preservative and (b) a diluent, wherein the powder can be reconstituted with the diluent prior to administration. In another embodiment, the present invention relates to a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide and mannitol and (b) a diluent, wherein the powder can be reconstituted with the diluent in the kit prior to administration. In another embodiment, the present invention relates to a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide, mannitol and optionally consisting of sweetener, flavoring agent and / or preservative, (b) diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. In another embodiment, the present invention relates to a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide and mannitol, (b) a diluent, which optionally comprises sweetener, flavoring agent and / or preservative, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. In a preferred embodiment, the kit comprises a dual-chamber bottle comprising: (a) the powder mixture of cyclophosphamide and mannitol, (b) water, and optionally comprising sweetener, flavoring agent, and / or preservative, wherein the powder can be reconstituted with the water in the kit prior to administration. The packaging kit of the present invention is designed such that the powder mixture of the bottle's stopper component is released into the water compartment of the bottle by applying pressure and squeezing the stopper and can therefore be reconstituted with water in the bottle prior to administration. In another embodiment, the present invention relates to a process for preparing a stable powder for oral solution comprising cyclophosphamide and one or more pharmaceutically acceptable excipients. In another embodiment, the present invention provides a process for preparing a stable powder for oral solution comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture into a conditioning container. In another embodiment, the present invention relates to a process for preparing a kit comprising a stable powder for oral solution and a diluent comprising the steps of: i) Mix cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing. i) Fill the required amount of powder mixture and water as a diluent into a kit. In another embodiment, the present invention relates to a method for treating malignant neoplasms in a pediatric patient comprising administering an oral composition frAznnn / zznz / E / YiAi from a kit comprising: (a) the powder for oral solution comprising a mixture of cyclophosphamide and mannitol, (b) diluent, wherein the said powder can be reconstituted with the diluent in the said kit prior to administration. In one of the preferred embodiments, the present invention provides a stable oral composition comprising cyclophosphamide and one or more pharmaceutically acceptable excipients, wherein said composition contains no more than 5% w / w of total cyclophosphamide impurity, more preferably no more than 3.5% of total cyclophosphamide impurity, and most preferably no more than 2% of total cyclophosphamide impurity, when stored under specified storage conditions. In one preferred embodiment, the present invention provides a stable oral composition comprising cyclophosphamide and one or more pharmaceutically acceptable excipients, wherein said composition contains no more than 0.2% w / w of an unknown cyclophosphamide impurity. In another embodiment, said composition contains no more than 0.1% w / w of an unknown cyclophosphamide impurity when stored under specified storage conditions. To further illustrate the present invention, the following examples are provided to enhance understanding. However, the scope of the present invention is not intended to be limited in any way, and it is quite evident to those skilled in the art, in light of the teachings of the present invention, that certain changes and modifications can be made without departing from the scope of the invention. Example 1: cyclophosphamide powder for oral solution bAznnn / zznz / E / YiAi Concentrations 150 mg / 15 ml 600 mg / 20 ml Ingredients Cyclophosphamide 150.0 600.0 Mannitol (Pearlitol SD 100) 146.4 585.6 Sucralose 3.0 12.0 Flavoring (forest fruits) 0.6 2.4 Total mixture 300.0 1200.0 Suspension vehicle Purified water qs up to 15 ml qs up to 20 ml Conditioning component Dual chamber bottle 1 ns 1 ns Powder filling kit 1 ne 1 ns Manufacturing process: Step 1: Mix cyclophosphamide, mannitol (Pearlitol SD100), sucralose and flavoring (forest fruits) for proper mixing. Step 2: Collect purified water in a container. Step 3: Fill the required amount of mixture and purified water into double-chamber bottles, using a powder filling machine and a continuous-moving liquid filling line with a capper. Example 2: cyclophosphamide powder for oral solution frAznnn / zznz / E / YiAi Concentrations 150 mg / 15 ml 600 mg / 20 ml Ingredients Cyclophosphamide 150.0 600.0 Mannitol (Pearlitol SD 100) 146.4 585.6 Suspension Vehicle Sucralose 3.0 12.0 Flavoring (forest fruits) 0.6 2.4 Purified water qs up to 15 ml qs up to 20 ml Conditioning Component Dual Chamber Bottle 1 ns 1 ns Powder Filling Kit 1 ne 1 ns Manufacturing process: Step 1: Mix cyclophosphamide and mannitol for proper mixing. Step 2: Collect purified water in a container and dissolve the sucralose and flavoring (forest fruits) in purified water by stirring. Step 3: Fill the required amount of mixture and suspension vehicle into twin-chamber bottles, using a powder filling machine and a continuous-moving liquid filling line with a capper. Example 3: Stability data for cyclophosphamide powder for oral solution Storage conditions: 25 °C / 60% RH Stability Stations Any Specified Individual Impurity Unknown Impurity Total Impurity Initial 0.022 ND 0.022 3 months 0.028 ND 0.028 The above results indicate enhanced stability of the powder for oral solution described in Example 2, in terms of lower impurities, which is within the limit according to the present invention. Furthermore, the powder mixture of the bottle cap component is released into the water compartment of the dual-chamber bottle by applying pressure and squeezing the cap. The powder is easily reconstituted with water in said bottle by gentle shaking to obtain an oral composition of cyclophosphamide. The oral composition obtained from cyclophosphamide can be provided to pediatric patients for the treatment of malignant neoplasms. frAznnn / zznz / E / YiAi Example 4: Preservative-free cyclophosphamide powder for oral solution Concentrations 150 mg / 15 ml 600 mg / 20 ml Powder component (mg / unit) Ingredients Cyclophosphamide 150 600 Mannitol (Pearlitol SD 100) 150 600 Total weight of powder mixture 300 1200 Suspension vehicle (mg / unit) Sucralose 3 12 Flavoring (forest fruits) 0.6 2.4 Purified water qs up to 15 ml qs up to 20 ml Manufacturing process: Step 1: Mix cyclophosphamide and mannitol for proper mixing. Step 2: Collect purified water (diluent) in a container and dissolve the sucralose and flavoring (forest fruits) in purified water by stirring. Step 3: Fill the required amount of mixture and suspension vehicle into twin-chamber bottles, using a powder filling machine and a continuous-moving liquid filling line with a capper. Example 5: Stability data for cyclophosphamide powder for oral solution Description Unknown Impurity Total Impurity Test Conditions not greater than 0.2% not greater than 5.0% 90-110% Initial ND 0.016 98.8 40 °C / 75% RH for 90 days 0.193 1.073 98.6 30 °C / 65% RH for 90 days 0.013 0.176 101.4 25 °C / 60% RH for 90 days 0.005 0.055 100.5 frAznnn / zznz / E / YiAi The oral powder for solution according to the present invention remains stable with no more than 5% total impurity when stored for at least three months at 40°C / 75% RH, 30°C / 65% RH and 25°C / 60% RH. Example 6: Cyclophosphamide powder for oral solution with preservative Unit Dose Strategy Multiple Dose Strategy Concentrations 150 mg / 15 ml 600 mg / 20 ml 150 mg / 5 ml; 40 ml 150 mg / 5 ml; 100 ml Powder Component (mg / unit) Ingredients Cyclophosphamide 150 600 1200 3000 Mannitol (Pearlitol SD 100) 150 600 1200 3000 Suspension Vehicle (mg / unit) Sucralose 3 12 24 60 Flavoring (forest fruits) 0.6 2.4 4.8 12 Methylparaben 6.50 26.00 52 130 Propylparaben 0.50 2.00 4 10 Purified Water qs up to 15 ml qs up to 20 ml qs up to 40 ml qs up to 100 ml frAznnn / zznz / E / YiAi The preceding Example is manufactured by the same process as Example-4. The oral compositions of the present invention can be administered as single-dose or multiple-dose formulations to adult and pediatric patients. Example 7: Stability results of cyclophosphamide powder for oral solution (150 mg / 15 ml) in a dual-chamber bottle Description Unknown impurity Total impurity Conditions not greater than 0.2% not greater than 5.0% 30 °C / 65-180 days 0.038 0.500 30 °C / 65-180 days (Inverted) 0.032 0.455 25 °C / 60-180 days 0.008 0.143 25 °C / 60-180 days (Inverted) 0.012 0.145 The oral powder for solution according to the present invention remains stable with no more than 5% total impurity when stored in double-chamber bottles for at least six months under conditions of 30°C / 65% RH and 25°C / 60% RH. Example 8: Stability results of cyclophosphamide powder for oral solution (150 mg / 15 ml) after reconstitution in a dual-chamber bottle Description Unknown Impurity Total Impurity Conditions not greater than 0.2% not greater than 5.0% Initial ND* 0.032 25°C / 60% RH for 12 hours ND* 0.723 25°C / 60% RH for 48 hours 0.101 3.268 2-8°C for 7 days ND 0.53 2-8°C for 14 days 0.033 1.309 *ND = Not Detected The reconstituted solution in a dual-chamber bottle remains stable for at least 48 hours after storage at 25°C / 60% RH and for at least 14 days after storage at 2-8°C.

Claims

1. A stable oral composition of cyclophosphamide comprising: (a) a powder mixture of cyclophosphamide and mannitol, (b) a diluent, wherein said composition is administered in the form of a powder for oral solution and said powder can be reconstituted with diluent prior to administration.

2. The stable powder for oral solution according to claim 1, wherein said powder comprising cyclophosphamide is not obtained by lyophilization.

3. The stable powder for oral solution according to claim 1, wherein the mannitol:cyclophosphamide ratio is not greater than approximately 1.2:1 and optionally consists of sweetener, flavoring agent and / or preservative.

4. The stable powder for oral solution according to claim 1, wherein the diluent is water and the powder mixture comprising cyclophosphamide can be reconstituted with water prior to administration.

5. The stable powder for oral solution according to claim 1, wherein the amount of cyclophosphamide is from 5 mg / ml to 50 mg / ml.

6. The stable powder for oral solution according to claim 1, wherein said powder comprises no more than 5% total cyclophosphamide impurity, when stored at 40°C / 75% RH, 30°C / 65% RH and 25°C / 60% RH for at least three months.

7. The stable oral composition according to claim 1, wherein said composition is in the form of a kit comprising: (a) the powder for oral solution comprising a powder mixture of cyclophosphamide, mannitol, (b) diluent and optionally consisting of sweetener, flavoring agent and / or preservative, wherein said powder can be reconstituted with the diluent in the kit prior to administration.

8. A stable powder for oral solution in the form of a kit comprising a dual-chamber bottle comprising (a) a powder mixture of cyclophosphamide and mannitol and (b) diluent; wherein said powder comprises no more than 5% total impurity of cyclophosphamide, when stored at 40°C / 75% RH, 30°C / 65% RH and 25°C / 60% RH for at least three months.

9. A process for preparing a kit comprising a dual-chamber bottle comprising stable powder for oral solution comprising the steps of: (a) mixing cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for proper mixing; (b) filling the required amount of powder mixture and diluent into a kit.

10. The stable oral composition according to claim 1, wherein said composition is administered to a pediatric patient for the treatment of malignant neoplasms, comprising: (a) the powder for oral solution comprising a mixture of cyclophosphamide, mannitol and, optionally, sweetener, flavoring agent and / or preservative for suitable mixing; (b) diluent, wherein said powder can be reconstituted with the diluent prior to administration.