PHARMACEUTICAL FORMULATION

• US 20160045436A1
• Filed: 08/14/2015
• Published: 02/18/2016
• Est. Priority Date: 08/15/2014
• Status: Abandoned Application

• Current Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: MOHR, Detlef, SOMMER, Florian
• Application Number:
  US14/826,240
• Publication Number:
  US 20160045436A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/009 Sachets, pouches characterised by the material or function of the envelope with gastric retention A61K9/0065; sachets which are not administered but function merely as a container are classified according to the content, e.g. sachets comprising powder for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/4816 Wall or shell material
• CPC Class Codes: A61M 5/284 comprising means for injection of two or more media, e.g. by mixing
• CPC Class Codes: A61P 35/00 Antineoplastic agents

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 NaH₂PO₄,

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 NaH₂PO₄.

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 NaH₂PO₄,

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 NaH₂PO₄.

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 NaH₂PO₄,

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 NaH₂PO₄.

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 NaH₂PO₄,

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 NaH₂PO₄.