PHARMACEUTICAL FORMULATION

Abstract

The present invention relates to pharmaceutical formulations of highly active drugs with limited shelf-life in aqueous media, suitable to be administered by a caregiver person to a patient avoiding or minimizing the risk of exposure, contact or contamination of the caregiver person with the active product ingredient (API), preferably an EGFR-TKI such as afatinib dimaleate.

Claims

1. A pharmaceutical kit comprising (i) at least one water-soluble pharmaceutical capsule containing a powder formulation of a drug comprising an active pharmaceutical ingredient (API) susceptible to hydrolytic decomposition, (ii) 50 to 250 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium contained in a pharmaceutically acceptable container 5 to 300% oversized by volume, for preparation of an oral solution comprising the API ready for administration with a shelf-life of the oral solution of up to 6 months at ambient temperature, and, optionally (iii) an oral syringe of suitable volume and graduation which can be connected with the bottle via an adapter plug, for dosing and administration, and, optionally, (iv) handling instructions comprising preparation of the oral API solution, measurement, withdrawal and administration of a dose.

2. The pharmaceutical kit of claim 1 comprising (i) at least one water-soluble pharmaceutical capsule with capsule shells made of HPMC, PVA (polyvinylalcohol), starch or Pullulan (α-1,4-; α-1,6-glucan) containing a powder formulation comprising an API susceptible to hydrolytic decomposition, (ii) 50 to 150 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium comprising (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, (b) 0.01-1% by weight of one or more pharmaceutically acceptable acids, (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, (e) optionally up to 10-20% by weight of one or more texture modifiers, (f) optionally one or more antioxidants, (g) optionally one or more stabilizers, (h) optionally one or more pH modifiers for adjustment of a physiologically acceptable pH, and (j) purified water as base solvent q.s. ad 100.0%, contained in a pharmaceutically acceptable container 5 to 100% oversized by volume for preparation of an oral solution comprising the API ready for administration with a shelf-life of the oral solution of up to 6 months at ambient temperature, and (iii) at least one oral syringe of 0.5 to 60 ml volume and suitable graduation which can be connected with the bottle via an adapter plug, for dosing and administration, and, optionally, (iv) handling instructions comprising preparation of the oral API solution, measurement, withdrawal and administration of a dose.

3. The pharmaceutical kit of claim 1, wherein the API is selected from the group consisting of gefitinib, erlotinib, pelitinib, neratinib, afatinib, HKI-357, CI-1033 (canertinib), WZ 3146, WZ 4002, WZ 8040, dacomitinib, CO-1686, AZD9291, HM781-36B, and HM61713, or pharmaceutically acceptable salts thereof.

4. The pharmaceutical kit of claim 2, wherein the natural sweeteners are selected from the group consisting of sucralose, glucose, fructose, xylitol, maltitol, mannitol, and sorbitol, and the artificial sweeteners are selected from the group consisting of aspartame, acesulfam-K, saccharin, saccharin-Na, Na-cyclamat, and stevia extract, the pharmaceutically acceptable acids are selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, sorbic acid and benzoic acid, the pharmaceutically acceptable flavors are selected from the group consisting of strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, and mint, the pharmaceutically acceptable salts or salty taste modifiers are selected from the group consisting of NaCl and NaH.sub.2PO.sub.4, the texture modifiers are selected from the group consisting of glycerol, soluble PVP (polyvinylpyrrolidone), and cellulose derivatives, the antioxidants are selected from the group consisting of ascorbic acid, butylhydroxytoluol (BHT) and butylhydroxyanisol (BHA), and the pH modifiers are selected from the group consisting of NaOH, HCL and NaH.sub.2PO.sub.4.

5. A pharmaceutically acceptable solvent comprising the combination of the following four taste masking principles (1) a pharmaceutically acceptable acid, (2) a pharmaceutically acceptable sweetener, (3) a pharmaceutically acceptable salt and (4) a pharmaceutically acceptable flavor.

6. The pharmaceutically acceptable solvent according to claim 5, comprising (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, (b) 0.01-1% by weight one or more pharmaceutically acceptable acids, (c) 0.01-1% by weight one or more pharmaceutically acceptable flavors, (d) 0.1-1% by weight one or more pharmaceutically acceptable salts or salty taste modifiers, (e) optionally up to 10-20% by weight one or more texture modifiers, (f) optionally one or more antioxidants, (g) optionally one or more stabilizers, (h) optionally one or more pH modifiers for adjustment of a physiologically acceptable pH, and (j) purified water as base solvent q.s. ad 100.0%.

7. The pharmaceutically acceptable solvent according to claim 6, wherein the natural sweeteners are selected from the group consisting of sucralose, glucose, fructose, xylitol, maltitol, mannitol, and sorbitol, and the artificial sweeteners are selected from the group consisting of aspartame, acesulfam-K, saccharin, saccharin-Na, Na-cyclamat, and stevia extract, the pharmaceutically acceptable acids are selected from hydrochloric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, sorbic acid and benzoic acid, the pharmaceutically acceptable flavors are selected from the group consisting of strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, and mint, the pharmaceutically acceptable salts or salty taste modifiers are selected from the group consisting of NaCl and NaH.sub.2PO.sub.4, the texture modifiers are selected from the group consisting of glycerol, soluble PVP (polyvinylpyrrolidone), and cellulose derivatives, the antioxidants are selected from the group consisting of ascorbic acid, butylhydroxytoluol (BHT) and butylhydroxyanisol (BHA), and the pH modifiers are selected from the group consisting of NaOH, HCL and NaH.sub.2PO.sub.4.

8. A method of administering a water-soluble pharmaceutical capsule containing a powder formulation of a drug comprising an API susceptible to hydrolytic decomposition to a patient who cannot swallow tablets, comprising dissolving the water-soluble capsule in 50 to 250 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium contained in a pharmaceutically acceptable container 5 to 300% oversized by volume, obtaining a defined dosage by withdrawing the required volume of the oral solution from the bottle using an oral syringe of suitable volume and graduation to be connected with the bottle via an adapter plug, and administering the defined dosage from the syringe orally to the patient.

9. The method according to claim 8, wherein the capsule shells are made of HPMC, PVA (polyvinylalcohol), starch or Pullulan (α-1,4-; α-1,6-glucan), and wherein the reconstitution medium has a volume of 50 to 150 ml and comprises the combination of the following four taste masking principles (1) a pharmaceutically acceptable acid, (2) a pharmaceutically acceptable sweetener, (3) a pharmaceutically acceptable salt and (4) a pharmaceutically acceptable flavor.

10. The method according to claim 9, wherein the reconstitution medium comprises (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, (b) 0.01-1% by weight of one or more pharmaceutically acceptable acids, (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, (e) optionally up to 10-20% by weight of one or more texture modifiers, (f) optionally one or more antioxidants, (g) optionally one or more stabilizers, (h) optionally one or more pH modifiers for adjustment of a physiologically acceptable pH, and (j) purified water as base solvent q.s. ad 100.0%.

11. The method according to claim 8, wherein the API is selected from the group consisting of gefitinib, erlotinib, pelitinib, neratinib, afatinib, HKI-357, CI-1033 (canertinib), WZ 3146, WZ 4002, WZ 8040, dacomitinib, CO-1686, AZD9291, HM781-36B, and HM61713, or pharmaceutically acceptable salts thereof.

12. The method according to claim 10, wherein the natural sweeteners are selected from the group consisting of sucralose, glucose, fructose, xylitol, maltitol, mannitol, and sorbitol, and the artificial sweeteners are selected from the group consisting of aspartame, acesulfam-K, saccharin, saccharin-Na, Na-cyclamat, and stevia extract, the pharmaceutically acceptable acids are selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, sorbic acid and benzoic acid, the pharmaceutically acceptable flavors are selected from the group consisting of strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, and mint, the pharmaceutically acceptable salts or salty taste modifiers are selected from the group consisting of NaCl and NaH.sub.2PO.sub.4, the texture modifiers are selected from the group consisting of glycerol, soluble PVP (polyvinylpyrrolidone), and cellulose derivatives, the antioxidants are selected from the group consisting of ascorbic acid, butylhydroxytoluol (BHT) and butylhydroxyanisol (BHA), and the pH modifiers are selected from the group consisting of NaOH, HCL and NaH.sub.2PO.sub.4.

13. The method according to claim 8, wherein the patient is a pediatric patient with an age of 6 months to 17 years, suffering from cancer, and the API is afatinib or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13, wherein the cancer is selected from the group consisting of recurrent or refractory rhabdomyosarcoma with ErbB receptor family deregulation and/or the specific tumour type independent from ErbB deregulation testing status, recurrent or refractory neuroectodermal tumours, diffuse intrinsic pontine glioma (DIPG), low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/primitive neuroectodermal tumour with ErbB receptor family deregulation and the specific tumour type independent from ErbB deregulation testing status.

15. A process for preparing a pharmaceutically acceptable solvent as a reconstitution medium for preparation of an oral solution of a drug ready for administration, comprising the steps of: successively dissolving the following four taste masking principles (1) a pharmaceutically acceptable acid, (2) a pharmaceutically acceptable sweetener, (3) a pharmaceutically acceptable salt and (4) a pharmaceutically acceptable flavor in purified water, adjusting to final weight by addition of purified water to obtain a bulk solution, optionally filtering the bulk solution, and optionally filling the bulk solution in a pharmaceutically acceptable container.

16. The process of claim 15 wherein the reconstitution medium comprises (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners; or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, (b) 0.01-1% by weight one or more pharmaceutically acceptable acids, (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, (e) optionally up to 10-20% by weight one or more texture modifiers, (f) optionally one or more antioxidants, (g) optionally one or more stabilizers, (h) optionally one or more pH modifiers for adjustment of a physiologically acceptable pH, and (i) purified water as base solvent, the process further comprising successively dissolving the components (a)-(h) in the purified water (i), adjusting to final weight by addition of the purified water as base solvent q.s. ad 100.0% to obtain a bulk solution, optionally filtering the bulk solution and optionally filling the bulk solution in pharmaceutically acceptable containers 5 to 100% oversized by volume.

17. The process of claim 16, wherein the natural sweeteners are selected from the group consisting of sucralose, glucose, fructose, xylitol, maltitol, mannitol, and sorbitol, and the artificial sweeteners are selected from the group consisting of aspartame, acesulfam-K, saccharin, saccharin-Na, Na-cyclamat, and stevia extract, the pharmaceutically acceptable acids are selected from the group consisting of hydrochloric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, sorbic acid and benzoic acid, the pharmaceutically acceptable flavors are selected from the group consisting of strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, and mint, the pharmaceutically acceptable salts or salty taste modifiers are selected from the group consisting of NaCl and NaH.sub.2PO.sub.4, the texture modifiers are selected from the group consisting of glycerol, soluble PVP (polyvinylpyrrolidone), and cellulose derivatives, the antioxidants are selected from the group consisting of ascorbic acid, butylhydroxytoluol (BHT) and butylhydroxyanisol (BHA), and the pH modifiers are selected from the group consisting of NaOH, HCL and NaH.sub.2PO.sub.4.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0049] The first aspect of the invention in a second embodiment is directed to a pharmaceutical kit comprising [0050] (i) at least one water-soluble pharmaceutical capsule with capsule shells made of HPMC, PVA (polyvinylalcohol), starch or Pullulan (α-1,4-; α-1,6-glucan) containing a powder formulation comprising an API susceptible to hydrolytic decomposition, preferably packed in a plastic bottle, a plastic blister or an alu blister, [0051] (ii) 50 to 150 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium comprising [0052] (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, [0053] (b) 0.01-1% by weight of one or more pharmaceutically acceptable acids, preferably acidic preservatives, [0054] (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, [0055] (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, [0056] (e) optionally up to 10-20% by weight of one or more texture modifiers, [0057] (f) optionally one or more antioxidants, such as ascorbic acid, butylhydroxytoluol (BHT) or butylhydroxyanisol (BHA), [0058] (g) optionally one or more stabilizers, such as EDTA, [0059] (h) optionally one or more pH modifiers such as a pharmaceutically acceptable acid, base or buffer, for adjustment of a physiologically acceptable pH, and [0060] (j) purified water as base solvent q.s. ad 100.0%, [0061] contained in a pharmaceutically acceptable container, such as a bottle, 5 to 100% oversized by volume preferably made of brown glass, for preparation of an oral solution comprising the API ready for administration with a shelf-life of the oral solution of up to 6 months at ambient temperature, and [0062] (iii) at least one oral syringe of 0.5 to 60 ml volume and suitable graduation which can be connected with the bottle via an adapter plug, for dosing and administration,

[0063] and, optionally, [0064] (iv) handling instructions comprising preparation of the oral API solution, measurement, withdrawal and administration of a dose.

[0065] Preferably the water-soluble pharmaceutical capsule has an approximate length of 20 to 30 mm to avoid inadvertent swallowing of the capsule, the capsule shells are made of HPMC and 1, 2, 3, 4 or 5 pharmaceutical capsules are packed in a polypropylene bottle with desiccant in the cap.

[0066] The second aspect of the invention in a second embodiment is directed to [0067] (ii) a suitable pharmaceutically acceptable solvent as a reconstitution medium for preparation of an oral solution ready for administration comprising an API susceptible to hydrolytic decomposition, with a shelf-life of the oral solution of up to 6 months at ambient temperature, comprising [0068] (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, [0069] (b) 0.01-1% by weight one or more pharmaceutically acceptable acids, preferably acidic preservatives, [0070] (c) 0.01-1% by weight one or more pharmaceutically acceptable flavors, [0071] (d) 0.1-1% by weight one or more pharmaceutically acceptable salts or salty taste modifiers, [0072] (e) optionally up to 10-20% by weight one or more texture modifiers, [0073] (f) optionally one or more antioxidants, such as ascorbic acid, butylhydroxytoluol (BHT) or butylhydroxyanisol (BHA), [0074] (g) optionally one or more stabilizers, such as EDTA, [0075] (h) optionally one or more pH modifiers such as a pharmaceutically acceptable acid, base or buffer, for adjustment of a physiologically acceptable pH, and [0076] (j) purified water as base solvent q.s. ad 100.0%.

[0077] The third aspect of the invention in a second embodiment is directed to [0078] (i) at least one water-soluble pharmaceutical capsule with capsule shells made of HPMC, PVA (polyvinylalcohol), starch or Pullulan (α-1,4-; α-1,6-glucan) containing a powder formulation comprising an API susceptible to hydrolytic decomposition, preferably packed in a plastic bottle, a plastic blister or an alu blister, for use in treatment of a patient who cannot swallow tablets, comprising dissolving the water-soluble capsule in [0079] (ii) 50 to 150 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium comprising the combination of the following four taste masking principles [0080] (1) a pharmaceutically acceptable acid, [0081] (2) a pharmaceutically acceptable sweetener, [0082] (3) a pharmaceutically acceptable salt and [0083] (4) a pharmaceutically acceptable flavor, [0084] contained in a pharmaceutically acceptable container, such as a bottle, 5 to 300% oversized by volume, for preparation of an oral solution comprising the API ready for administration, [0085] or, more specifically, 50 to 150 ml of a suitable pharmaceutically acceptable solvent as a reconstitution medium comprising [0086] (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, [0087] (b) 0.01-1% by weight of one or more pharmaceutically acceptable acids, preferably acidic preservatives, [0088] (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, [0089] (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, [0090] (e) optionally up to 10-20% by weight of one or more texture modifiers, [0091] (f) optionally one or more antioxidants, such as ascorbic acid, butylhydroxytoluol (BHT) or butylhydroxyanisol (BHA), [0092] (g) optionally one or more stabilizers, such as EDTA, [0093] (h) optionally one or more pH modifiers such as a pharmaceutically acceptable acid, base or buffer, for adjustment of a physiologically acceptable pH, and [0094] (j) purified water as base solvent q.s. ad 100.0%, [0095] contained in a pharmaceutically acceptable container, such as a bottle, 5 to 300% oversized by volume, for preparation of an oral solution comprising the API ready for administration, [0096] and [0097] (iii) administration of a defined dosage by withdrawing the required volume, e.g. 0.5 to 60 ml, of the oral solution from the bottle using an oral syringe of suitable volume and graduation to be connected with the bottle via an adapter plug, and administration of the defined dosage from the syringe orally to the patient.

[0098] Preferably the pharmaceutically acceptable solvent as a reconstitution medium is an aqueous solvent.

[0099] The fourth aspect of the invention in a second embodiment is directed to a process for preparing [0100] (ii) a suitable pharmaceutically acceptable solvent as a reconstitution medium for preparation of an oral solution of a drug ready for administration, comprising an API susceptible to hydrolytic decomposition, with a shelf-life of the oral solution of up to 6 months at ambient temperature, comprising the steps

[0101] successively dissolving [0102] (a) 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners or 0.1% -70% by weight of one or more pharmaceutically acceptable natural sweeteners or 0.1% -65% by weight of one or more pharmaceutically acceptable natural sweeteners and 0.1% -5% by weight of one or more pharmaceutically acceptable artificial sweeteners, [0103] (b) 0.01-1% by weight one or more pharmaceutically acceptable acids, preferably acidic preservatives, [0104] (c) 0.01-1% by weight of one or more pharmaceutically acceptable flavors, [0105] (d) 0.1-1% by weight of one or more pharmaceutically acceptable salts or salty taste modifiers, [0106] (e) optionally up to 10-20% by weight one or more texture modifiers, [0107] (f) optionally one or more antioxidants, such as ascorbic acid, butylhydroxytoluol (BHT) or butylhydroxyanisol (BHA), [0108] (g) optionally one or more stabilizers, such as EDTA, [0109] (h) optionally one or more pH modifiers such as a pharmaceutically acceptable acid, base or buffer, for adjustment of a physiologically acceptable pH,

[0110] in purified water as base solvent, preferably with stirring at a temperature of 20 to 60° C., preferably 20 to 40° C., and adjusting to final weight by addition of purified water as base solvent q.s. ad 100.0% to obtain a bulk solution,

[0111] optionally filtering the bulk solution and

[0112] optionally filling the bulk solution in pharmaceutically acceptable containers, such as bottles, 5 to 100% oversized by volume, preferably 5 to 30% or specifically 25% oversized, and close the containers.

[0113] A container or bottle 100% oversized by volume means that 100 ml of bulk solution is filled in a container or bottle of 200 ml volume.

[0114] The oral solution ready for administration comprising an API susceptible to hydrolytic decomposition may have a shelf-life of the oral solution of up to 6 months, of up to 3 months, of up to 4 weeks or of up to one week at ambient temperature.

[0115] APIs suitable to be used in the context of the invention may be selected from oncological small-molecule (NCE) drugs mentioned hereinbefore, preferably from reversible or irreversible binding EGFR inhibitors such as gefitinib, erlotinib, pelitinib, neratinib, afatinib, HKI-357, CI-1033 (canertinib), WZ 3146, WZ 4002, WZ 8040, dacomitinib, CO-1686, AZD9291, HM781-36B, and HM61713, or pharmaceutically acceptable salts thereof.

[0116] A second preferred subgroup of APIs suitable to be used in the context of the invention is selected from gefitinib, erlotinib, neratinib, afatinib, CI-1033 (canertinib), dacomitinib, CO-1686, and AZD9291, and HM61713, or pharmaceutically acceptable salts thereof.

[0117] A third preferred subgroup of APIs suitable to be used in the context of the invention is selected from neratinib, afatinib, dacomitinib, CO-1686 and AZD9291, whereas afatinib is particularly preferred, or pharmaceutically acceptable salts thereof. Most preferred is the dimaleate salt of afatinib (BIBW 2992 MA2).

[0118] Suitable sweeteners as components of the reconstitution medium may be selected from natural sweeteners such as sucrose, glucose, fructose, xylitol, maltitol, mannitol, and sorbitol, or from artificial sweeteners such as sucralose, aspartame, acesulfam-K, saccharin, saccharin-Na, Na-cyclamat, stevia extract and the like. A preferred sweetener is sucralose.

[0119] Suitable preservatives as components of the reconstitution medium may be selected from sorbic acid, K-sorbate, Na-benzoate, benzoic acid, parabens, methyl parabens, benzalkoniumchloride and the like. A preferred preservative is sorbic acid.

[0120] Suitable flavors as components of the reconstitution medium may be selected from e.g. strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, mint and the like, which may be used also in combination of up to 3 different flavors within a reconstitution medium. Preferred flavors are strawberry, cream, cacao and vanilla, or the combination of cream and strawberry flavor, as well as the combination of cacao and vanilla flavor.

[0121] Suitable salty taste modifiers as components of the reconstitution medium may be selected from NaCL or NaH.sub.2PO.sub.4, and the like. A preferred salty taste modifier is NaCL.

[0122] Suitable texture modifiers as components of the reconstitution medium may be selected from e.g. glycerol, soluble PVP, or cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose or hydroxypropylmethylcellulose, and the like.

[0123] Suitable antioxidants as components of the reconstitution medium may be selected from ascorbic acid, butylhydroxytoluol (BHT) and butylhydroxyanisol (BHA) and the like. A preferred stabilizer is EDTA. As pH modifiers may be used suitable amounts of NaOH, HCL or NaH.sub.2PO.sub.4.

[0124] Suitable capsules that dissolve at room temperature within 30 min under occasionally shaking in the reconstitution medium according to the invention are, for instance, transparent HPMC hard shell capsules size 00, e.g. Vcaps Plus® available from Capsugel. Gelatine shells cannot be dissolved at room temperature since these capsules are only gelling. The composition of the reconstitution medium enables taste masking of bitter API. 100 ml of the reconstitution medium may be contained in a 125 ml bottle, with some free head space necessary to apply shear forces to the capsule during the dissolution process. Preferably the bottle is made from brown glass.

[0125] The handling instruction mentioned hereinbefore may comprise for example:

[0126] For preparation of the oral solution ready for administration:

[0127] Open the bottle containing the solvent for oral solution;

[0128] Open the plastic bottle containing capsules with the active ingredient for oral solution;

[0129] Transfer a defined number of capsules carefully into the solvent;

[0130] Mount the plastic adapter on the glass bottle and close the bottle with the screw cap;

[0131] Wait 15 min and shake the bottle vigorously for at least 10 seconds;

[0132] Wait 10 min and shake the bottle again vigorously for at least 10 seconds;

[0133] After waiting 5 min, gently shake the solution. The solution is ready to use. The solution might contain undissolved particles resulting from excipients of the capsule formulation which do not affect the quality of the drug product.

[0134] The handling instruction for measurement and withdrawal of a dose may comprise:

[0135] Gently shake the bottle;

[0136] Open the bottle;

[0137] Insert the oral syringe in the adapter (optionally referring to a picture);

[0138] Rotate the bottle including adapter and syringe upside down (optionally referring to a picture);

[0139] Withdraw the required volume. If air bubbles are visible, empty the syringe into the bottle and repeat the withdrawal of the required volume.

[0140] Administer the bubble-free solution orally to the patient.

[0141] Any of the formulation options defined hereinbefore exhibit unexpected good matching results >95% in placebo taste match model of e-tongue measurements, typical average match values have been seen in a range of up to 80%, particularly those comprising the combination of the four taste masking principles acid plus salt plus sweetener plus flavor revealed superior results, and specifically those described in the Examples.

[0142] In any aspects of the invention the patient may be a pediatric patient suffering from cancer, more specifically from

[0143] recurrent or refractory rhabdomyosarcoma with ErbB receptor family deregulation and/or the specific tumour type independent from ErbB deregulation testing status, or from

[0144] recurrent or refractory neuroectodermal tumours, i.e. high grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), low grade astrocytoma, neuroblastoma, ependymoma, medulloblastoma/primitive neuroectodermal tumour with ErbB receptor family deregulation and/or the specific tumour type independent from ErbB deregulation testing status,

[0145] rarely occurring in adult patients,

[0146] to be treated with a drug comprising afatinib or a pharmaceutically acceptable salt thereof, such as afatinib dimaleate, as the API, which is susceptible for hydrolytic decomposition.

[0147] The pediatric patient is a patient with an age of 6 months to 17 years, with defined subgroups of 6 months to 1 year, 6 months to 2 years, 6 months to 1 year, 1 to 3 years, 2 to 4 years, 4 to 8 years, and 8 to 17 years.

[0148] Afatinib film-coated tablets as described in WO 2009/147238 and afatinib capsules and solvent for oral solution according to the subject invention are considered age appropriate formulations covering the needs for treatment of pediatric patients of 6 months to 17 years with adequate dosing flexibility and patient convenience. The oral route of administration and once daily posology allow administration by caregivers outside the hospital setting to minimize the impact on daily activities, incl. participation in public life, e.g. school, of the paediatric patients. The intended dosing schedule ranging from 4 mg, applied as oral solution, to 60 mg, either applied as film-coated tablets or oral solution, is therefore well covered by the two formulations.

[0149] Volumes between 1.0 mL and 15.0 mL (equivalent to 4 mg to 60 mg dosage of afatinib), specifically of 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0, 12.0, 13.0, 14.0, and 15.0 mL are expected to be applied, preferably once daily. Any of these dosages may be used as the total daily dosage for a patient, depending on the age and the specific needs of the patient. The daily total dosage of the drug may be separated into multiple single dosages administered over the day, preferably 2 or 3 single dosages. Dosing and administration is performed with an oral syringe suitable for the intended volume. The syringe is to be connected to the bottle via an adapter plug.

[0150] As decreased bioavailability of afatinib has been observed in adults ad fed state, the oral solution is not intended to be administered with food or drinks.

[0151] A relative bioavailability trial was performed in healthy adult volunteers comparing afatinib dimaleate administered as a drinking solution and as a 20 mg film-coated tablet (afatinib dimaleate, dose provided as the afatinib content). In this trial no significant differences were observed in the relative bioavailability of afatinib administered as a drinking solution and as a 20 mg film-coated tablet. In the drinking solution used in the trial the active substance was completely dissolved. The excipients in the drinking solution are not considered to have any impact on the pharmacokinetic behavior of afatinib.

[0152] The conclusions drawn for the drinking solution used for the study are considered to be representative for the pediatric formulation.

EXAMPLES

Example 1

[0153] Composition of afatinib 200 mg capsules (transparent HPMC hard shell capsule size 00 (Vcaps Plus® of Capsugel) containing dry-granulated BIBW 2992 MA2 as a white to slightly yellowish powder formulation):

TABLE-US-00001 Ingredient Amount [mg/capsule] Function Capsule fill Afatinib dimaleate   295.6 Active ingredient (Afatinib free base) (200) Lactose, monohydrate   274.4 Filler Crospovidone   18.0 Disintegrant Magnesium stearate   12.0 Lubricant Subtotal   600.0 Capsule shell HPMC capsule size 00, 118 Capsule shell transparent Subtotal 118 Total   718.0

[0154] The dry-granulated BIBW 2992 MA2 powder formulation can be prepared in analogy as disclosed in WO 2009/147238.

[0155] Preferably two afatinib 200 mg capsules are packed in a 60 ml child-resistant polypropylene bottle with desiccant in the cap.

Example 2

[0156] General solvent composition (reconstitution medium), Strawberry-cream reco-solvent option (125 ml brown glass bottle with child resistant cap filled with 100 ml of a clear solution).

TABLE-US-00002 Composition Quantity range Sweetener (artificial) Depending on type e.g. Sucralose, Aspartame, Acesulfam-K, 0.1%-5% Saccharin-Na, Na-cyclamat etc. standalone or in combination with natural sweetener Natural sweetener (non cariogenic) up to 60-70% standalone or e.g. Maltitol, Sorbitol, Xylitol, Mannitol, in combination with Preservative artificial sweetener 0.01-1% e.g. Sorbic acid, Na-Benzoate, Benzoic acid, acc. to specific properties Parabens Antioxidants Typically 0.01-0.5% e.g. BHT, BHA, Ascorbic acid Typically 0.01-0.1% Stabilizer Typically up to 0.15% e.g. EDTA Flavor Typically 0.01-1% e.g. strawberry, raspberry, currant, cream, cacao, chocolate, vanilla, cherry, tutti frutti, mint, also in combination of up to 3 different flavors Salty taste modifier 0.1-1% (e.g. NaCL, NaH.sub.2PO.sub.4 etc.) preferred 0.45-0.9% Texture modifier Depending on type up to (e.g., Glycerol, Cellulose derivatives etc.) 10-20% pH-modifier Amount sufficient to keep e.g. HCL, NaOH, suitable buffer systems formulation target pH after reconstitution at a range between pH 2.5-4.0 Purified water as base solvent q.s. ad final fill weight

Example 3

[0157] Solvent composition (reconstitution medium), Strawberry-cream reco-solvent option (125 ml brown glass bottle with child resistant cap filled with 100 ml of a clear solution).

TABLE-US-00003 [mg/ Reference Ingredients [g/bottle] bottle] Function to standards Sucralose 0.50 5.00 Sweetener USP-NF Sorbic acid 0.05 0.50 Preservative Ph. Eur./ USP-NF Sodium chloride 0.90 9.00 Taste modifier Ph. Eur./USP Cream flavor 0.10 1.00 Flavor Company standard Strawberry flavor 0.10 1.00 Flavor Company standard Purified water 99.05 990.50 Solvent Ph. Eur./USP Total weight 100.70

Example 4

[0158] Solvent composition (reconstitution medium), strawberry-cream reco-solvent option (125 ml brown glass bottle with child resistant cap filled with 100 ml of a clear solution).

TABLE-US-00004 Low dose preservative High dose preservative (0.05%) (0.15%) Composition g/bottle g/bottle Sucralose 0.5 0.5 Sorbic acid 0.05 0.15 Sodium chloride 0.9 0.9 Cream flavor 0.1 0.1 Strawberry flavor 0.1 0.1 Purified water q.s. ad 100.0 ml q.s. ad 100.0 ml

[0159] Strawberry/cream flavor variant showed excellent taste masking efficiency.

Example 5

[0160] Solvent composition (reconstitution medium), cacao-vanilla reco-solvent option (125 ml brown glass bottle with child resistant cap filled with 100 ml of a clear solution).

TABLE-US-00005 Low dose preservative High dose preservative (0.05%) (0.15%) Composition g/bottle g/bottle Sucralose 0.5 0.5 Sorbic acid 0.05 0.15 Sodium chloride 0.45 0.45 Cacao flavor 0.05 0.05 Vanilla flavor 0.2 0.2 Purified water q.s. ad 100.0 ml q.s. ad 100.0 ml

Example 6

Preparation of Afatinib Dimaleate Oral Solution Ready for Administration

[0161] The oral solution is prepared by dissolving two capsules in the supplied 100 ml solvent in the 125 ml brown glass bottle, resulting in an afatinib concentration of 4 mg/ml. The capsules must not be opened nor swallowed. The capsules are put into the bottle containing the solvent. The bottle is closed, and the capsules are dissolved by shaking the bottle manually in intervals.

[0162] The prepared solution is turbid and contains undissolved particles. The active substance is completely dissolved; the undissolved particles derive from the excipients (e.g. magnesium stearate, crospovidone) and do not impact the quality of the product or the dosing accuracy. The solution is stable for 4 weeks at 25° C. after preparation.

Example 7

Administration of Oral Solution

[0163] The prepared oral solution contains 4 mg/ml of afatinib. Based on body surface area dosage volumes between 1.0 and 15 ml might be applied. Dosing and administration is planned to be done using an oral syringe suitable for the intended volume. The syringe can be connected with the bottle via an adapter plug. The syringe should have a volume syringe of 0.5 to 60 ml volume and suitable graduation, e.g. in 0.1, 0.5 or 1.0 ml steps. Single use of an oral syringe (12 mL maximal volume) is suitable. For the possible use of dosing volumes greater than 12 mL the splitting of the dose re-using the pipette is considered acceptable. The syringe is foreseen to be cleaned with water after every use by filling and purging.

Example 8

Relative Bioavailability of Afatinib Final Formulation Tablet Compared to Oral Solution

[0164] A relative bioavailability (BA) trial was conducted to evaluate the relative BA of the 20 mg afatinib film-coated tablet to a 20 mg afatinib drinking solution. Geometric mean plasma concentrations of afatinib were slightly higher after administration of the drinking solution compared with the 20 mg film-coated tablet. However, the shape of the afatinib plasma concentration-time profiles was similar for the 20 mg film-coated tablet and the drinking solution tested. Maximum plasma concentrations were reached after 5 h (median t.sub.max) for both formulations. Also the mean residence time after peroral intake (MRT po) of afatinib was comparable for both formulations tested (20 mg film-coated tablet: 35.9 h versus drinking solution: 34.2 h), which might suggest that the mean absorption time of afatinib was equal for both formulations.

[0165] Intra-individual comparisons of C.sub.max and AUC 0-∝ displayed a strong overlap of individual Cmax and AUC 0-∝ values between the 20 mg film-coated tablet and the drinking solution. The statistical evaluation of the relative bioavailability results are summarized in the table below. It should be noted that the trial was not powered to show bioequivalence between the formulations (N=22 healthy volunteers were treated in a cross-over design; considering the variability in PK observed in this trial, N=84 healthy volunteers would have been required to have a targeted power of 90% to show bioequivalence assuming a ratio of 0.95 for both formulations).

[0166] In this trial no significant differences were observed in the relative bioavailability of afatinib administered as a drinking solution and as a 20 mg film-coated tablet

[0167] Summary of Results from the Relative Bioavailability Trial 1200.35 20 mg Film-Coated Tablet Versus Drinking Solution

TABLE-US-00006 Geometric Lower Upper mean ratio 90% CI 90% CI Test Reference Parameter (%) (%) (%) 20 mg film- Drinking C.sub.max 85.31 68.75 105.88 coated solution 20 mg [ng/ml] tablet (FF per bottle AUC.sub.0-∞ 92.24 76.30 111.51 tablet) [ng .Math. h/ml]

[0168] The 20 mg film-coated tablets (FF tablet) used in the trial is identical to the commercial 20 mg film-coated tablets except for the color of the film-coat and the embossment. Both formulations have been demonstrated to have the same dissolution profiles and are therefore expected to have the same pharmacokinetic behavior.

[0169] The drinking solution containing 20 mg of afatinib per bottle used in the trial was prepared by dissolving the drug substance in 80 ml of a solvent consisting of hydroxyethyl cellulose, poloxamer 188 and purified water. The active substance is completely dissolved. The excipients contained in the drinking solution did not show an impact on the pharmacokinetic behavior of afatinib.