EP4034120A1 - Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient - Google Patents

Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient

Info

Publication number
EP4034120A1
EP4034120A1 EP20868515.6A EP20868515A EP4034120A1 EP 4034120 A1 EP4034120 A1 EP 4034120A1 EP 20868515 A EP20868515 A EP 20868515A EP 4034120 A1 EP4034120 A1 EP 4034120A1
Authority
EP
European Patent Office
Prior art keywords
weight
solid oral
oral pharmaceutical
pharmaceutical formulation
formulation according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20868515.6A
Other languages
German (de)
French (fr)
Other versions
EP4034120A4 (en
Inventor
Arzu PALANTOKEN
Damla TURKOGLU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4034120A1 publication Critical patent/EP4034120A1/en
Publication of EP4034120A4 publication Critical patent/EP4034120A4/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutically acceptable excipient.
  • Phenylketonuria is a rare condition where babies are born unable to break down an amino acid called phenylalanine. This causes phenylalanine to build up. When phenylalanine levels get too high, it can cause damage to the brain. This can lead to intellectual and developmental disabilities.
  • Phenylalanine is found in foods that contain protein. PKU is manageable, mostly through your diet. The key to living with PKU successfully is finding it early. That is why all babies in the United States are screened for the disease at birth.
  • PKU is an inherited disease. This means it is passed down through the genes of the mother and father. It is caused by mutations in the gene that helps make an enzyme called phenylalanine hydroxylase. This enzyme helps break down phenylalanine. When this gene doesn’t work right, the body can’t break down phenylalanine. It starts to build up and causes damage to nerve cells in the brain.
  • microcephaly Smaller than normal head size
  • the U.S. Food and Drug Administration has approved the medicine sapropterin dihydrochloride (Kuvan®) for the treatment of PKU.
  • Kuvan can help the body break down phenylalanine.
  • Sapropterin dihydrochloride (Kuvan® [BioMarin, CA, USA]) is the first and only registered synthetic form of the naturally occurring enzyme cofactor, BH4 (5, 6,7,8- tetrahydrobiopterin) Sapropterin is an orally active, synthetic dihydrochloride salt formulation of the Biologically active 6R-diastereoisomer of BH4 (5, 6,7,8- tetrahydrobiopterin)
  • PKU is characterized by a defect in the PAH (Phenylalanine hydroxylase) enzyme, residual enzymatic activity may be present in some patients.
  • sapropterin may act like a chemical chaperone to promote the normal metabolism of Phe(Phenylalanine) and lower its concentration in the blood in a subset of patients who are BH4 responsive. Sapropterin may be used to assist in the control of Phe concentrations. It provides the opportunity for patients who respond to BH4 to adjust their diet, thereby allowing a greater intake of Phe or even coming off of their Phe-restrictive diet.
  • the overall frequency of BH4 responsiveness across Europe is estimated to be 55-62%, based on projections made using genetic allelic data for BH4 responsiveness, although responsiveness can only be determined by a response test.
  • Sapropterin dihydrochloride has the following structural formula:
  • compositions comprising selected and stable crystal forms of (6R)-L-erythro- tetrahydrobiopterin dihydrochloride or a hydrate thereof and a pharmaceutically acceptable carrier.
  • the patent EP1757293B1 of Daiichi Sankyo discloses an effective sapropterin hydrochloride preparation that is highly stable during storage and can administer sapropterin hydrochloride, an effective therapeutic agent for the treatment of tetrahydrobiopterin-responsive hyperphenylalaninemia, to patients of a wide range of ages, ranging from infants to adults, in a single preparation.
  • compositions of the invention may comprise a stable, crystalline form of BH4 that is stable at room temperature for more than 8 hours and a pharmaceutically acceptable carrier, diluent or excipient.
  • Exemplary stable tablets of the invention have been prepared using a dry tableting process and have been shown to have a shelf-life of at least 6 to 9 months at room temperature.
  • the patent application EP2680848A1 of Dipharma discloses stable pharmaceutical compositions comprising tetrahydrobiopterin and at least one stabilizing agent. Particularly the present invention relates to stable compositions of sapropterin dihydrochloride. Antioxidants that stabilize tetrahydrobiopterin; with the weight ratio of the antioxidant to active ranging from 0.2 - 1.5.
  • the patent application CN104257623A patent of Guangdong Zhongsheng pharmaceutical company discloses an effervescent tablet containing sapropterin dihydrochloride.
  • Sapropterin dihydrochloride exhibits polymorphism and many crystalline forms have been identified; among all the polymorphic forms, Form B was identified to be thermodynamically stable crystalline anhydrate form. Polymorph form B is a very stable crystalline form, that can be easily filtered off, dried and ground to particle sizes desired for pharmaceutical formulations. These outstanding properties renders polymorph form B especially feasible for pharmaceutical application.
  • Sapropterin dihydrochloride is currently available as oral soluble tablets of 100mg and 100mg-500mg powder packets under the brand name KuvanTM. It is marketed by BioMarin in the US and Merck Serono in Europe. KuvanTM has been designated as an orphan medication since hyperphenylalaninemia is a rare disease. KuvanTM is indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin responsive phenylketonuria. It is to be used in conjunction with phenylalanine restricted diet.
  • sapropterin dihydrochloride In patients with phenylketonuria the role of sapropterin dihydrochloride is to enable endogenous phenylalanine hydroxylase activity and to partially restore oxidative metabolism of phenylalanine, resulting in decreased blood phenylalanine levels. In patients with BH4 deficiency, sapropterin dihydrochloride is proposed to restore endogenous phenylalanine hydroxylase activity by providing an exogenous source of the missing cofactor.
  • Tetrahydrobiopterin is an unstable compound; at ambient temperature it is prone to autoxidation in the presence of molecular oxygen. Tetrahydrobiopterin is also very hygroscopic. Therefore, the development of stable oral composition comprising tetrahydrobiopterin that is prone to degradation at room temperature is a challenging task.
  • compositions of sapropterin comprising stabilizers in variety of ratios
  • stability of these compositions is low at room temperature or 40°C/75% relative humidity and need to be stored under refrigeration.
  • Low stability of such tetrahydrobiopterin compositions is commercially undesirable and significant degradation due to improper storage could hinder therapy. Need therefore, exists for preparations of tetrahydrobiopterin that are more stable and retain desired amount of active over a longer time even when not refrigerated.
  • the amount and type of stabilizer and other excipients present in the compositions of sapropterin determine the stability of the active and compositions thereof. Too little or too much stabilizer can affect the stability of the compositions of sapropterin and an appropriate amount of stabilizer must therefore be present in these compositions.
  • the stable formulations of sapropterin dihydrochloride according to the present invention thus provide desired amount of active over the entire shelf life of the product.
  • the main object of the present invention is to provide solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutically acceptable excipient with desired stability and bioavailability.
  • sapropterin dihydrochloride refers to not only sapropterin dihydrochloride, but also its other pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
  • the amount of sapropterin dihydrochloride is between 15.0-40.0%, preferably 20.0- 30.0%, more preferably 25.0-30.0% by weight of the solid oral pharmaceutical formulation.
  • said the solid oral pharmaceutical formulation one or more pharmaceutically acceptable excipient which is selected from antioxidants, binders, disintegrants, lubricants, glidants, diluents or mixtures thereof.
  • Suitable antioxidants are selected from the group comprising alpha tocopherol (Vitamin E), quercetine, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbyl palmitate, alpha lipoic acid, erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, citric acid, thymol or mixtures thereof.
  • antioxidants are selected from quercetine, alpha tocopherol(vitamin E), butylhydroxyanisole or butylhydroxytoluene or mixtures thereof.
  • the amount of antioxidant is between 5.6-6.4% by weight of the solid oral pharmaceutical formulation.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
  • the amount of glidant is between 0.1% and 1.0% by weight of the formulation, preferably it is between 0.2% and 1.0% by weight, more preferably it is between 0.5% and 1.0% by weight of the solid oral pharmaceutical formulation.
  • the glidant is colloidal silicon dioxide.
  • Suitable binders are selected from the group comprising lactose anhydrous, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagenselatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
  • binders are used to achieve the desired dissolution profile, especially, when the amount of binder is between 1.0% and 50.0%, the solid oral pharmaceutical formulation shows desired dissolution profile.
  • the amount of binder is between 1.0% and 50.0%, 5.0% and 50.0%, 10.0% and 50.0%, 20.0% and 50.0% by weight of the solid oral pharmaceutical formulation.
  • the binder is lactose anhydrous.
  • Suitable disintegrants are selected from the group comprising polyvinyl pyrrolidone (crospovidone), crospovidone CL-Superfine (kollidon CL-Superfine), povidone, cross- linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
  • polyvinyl pyrrolidone crospovidone
  • CL-Superfine crospovidone CL-Superfine
  • povidone cross- linked carboxymethyl cellulose
  • the amount of disintegrant is between 2.0% and 8.0%, 2.0% and 7.0%, 2.0% and 6.0%, 2.0% and 5.0% by weight of the solid oral pharmaceutical formulation.
  • the disintegrant is sodium starch glycolate.
  • Suitable lubricants are selected from the group comprising from magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
  • the amount of lubricant is between 0.25% and 5.0%, 0.5% and 4.5%, 1.0% and 4.0%, 2.0% and 3.0% by weight of the solid oral pharmaceutical formulation.
  • the lubricant is magnesium stearate.
  • Suitable diluents which is selected from the group comprising, microcrystalline cellulose, dibasic calcium phosphate, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • the amount of diluent is between 20.0% and 90.0%, 20.0% and 80.0%, 20.0% and 70.0%, 20.0% and 60.0%, 20.0% and 30.0% by weight of the solid oral pharmaceutical formulation.
  • the diluent is microcrystalline cellulose.
  • the solid oral pharmaceutical formulation is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solids.
  • the solid oral pharmaceutical formulation is in the form of tablets or capsule.
  • the solid oral pharmaceutical formulation may be prepared by conventional technology well known to those skilled in the art such as direct compression, dry granulation, wet granulation and the like.
  • direct compression active agent and excipients are mixed, sieved and compressed into dosage forms or if the capsule is to be made, powder mixture is filled into gelatin capsules.
  • wet granulation the ingredients are mixed and granulated with a granulation liquid. The granulation process provides agglomerates with a desired homogeneity. The mixture is sieved and optionally mixed with additional excipients. Finally, it is compressed into dosage forms or if the capsule is to be made, powder mixture is filled into gelatin capsules.
  • According to another embodiment of the present invention is to provide a stable solid oral pharmaceutical formulation by a simple preparation process.
  • the pharmaceutical formulations of the present invention can be prepared in a fast, efficient, commercially cost low and plant-friendly manufacturing process. A desired dissolution profile of the solid oral pharmaceutical formulation is obtained.
  • Example 1 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression
  • Example 2 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression
  • Example 3 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression Process (Direct compression/ Capsule filling) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous,
  • Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
  • Example 4 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression Process (Direct compression/Capsule filling)
  • direct compression Process Direct compression/Capsule filling
  • Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
  • Example 5 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation * * q.s.: quantity sufficient
  • Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
  • Example 6 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
  • Example 7 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
  • Example 8 Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
  • Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.

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Abstract

The present invention relates to solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient.

Description

DESCRIPTION
SOLID ORAL PHARMACEUTICAL FORMULATIONS COMPRISING SAPROPTERIN DIHYDROCHLORIDE AND AT LEAST ONE PHARMACEUTICAL
EXCIPIENT
Field of the invention
The present invention relates to solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutically acceptable excipient.
Background of the invention
Phenylketonuria (PKU) is a rare condition where babies are born unable to break down an amino acid called phenylalanine. This causes phenylalanine to build up. When phenylalanine levels get too high, it can cause damage to the brain. This can lead to intellectual and developmental disabilities.
Phenylalanine is found in foods that contain protein. PKU is manageable, mostly through your diet. The key to living with PKU successfully is finding it early. That is why all babies in the United States are screened for the disease at birth.
PKU is an inherited disease. This means it is passed down through the genes of the mother and father. It is caused by mutations in the gene that helps make an enzyme called phenylalanine hydroxylase. This enzyme helps break down phenylalanine. When this gene doesn’t work right, the body can’t break down phenylalanine. It starts to build up and causes damage to nerve cells in the brain.
Initially in newborns there are no symptoms. But within a few months of birth, depending on the severity of the disease, symptoms begin to show. These include:
• Smaller than normal head size (called microcephaly)
Hyperactivity • A musty or mouse-like odor in urine, breath, or skin
• Lighter skin, hair, and eyes than their siblings
• Skin disorders such as eczema
• Jerking movements of the arms or legs · Tremors
• Seizures
• Delayed development
• Behavioral problems
• Psychiatric disorders Permanent intellectual disability
If PKU is not controlled through changes in diet, it can cause severe intellectual and developmental disability.
The U.S. Food and Drug Administration has approved the medicine sapropterin dihydrochloride (Kuvan®) for the treatment of PKU. Kuvan can help the body break down phenylalanine.
Sapropterin dihydrochloride (Kuvan® [BioMarin, CA, USA]) is the first and only registered synthetic form of the naturally occurring enzyme cofactor, BH4 (5, 6,7,8- tetrahydrobiopterin) Sapropterin is an orally active, synthetic dihydrochloride salt formulation of the Biologically active 6R-diastereoisomer of BH4 (5, 6,7,8- tetrahydrobiopterin) Although PKU is characterized by a defect in the PAH (Phenylalanine hydroxylase) enzyme, residual enzymatic activity may be present in some patients. Thus, sapropterin may act like a chemical chaperone to promote the normal metabolism of Phe(Phenylalanine) and lower its concentration in the blood in a subset of patients who are BH4 responsive. Sapropterin may be used to assist in the control of Phe concentrations. It provides the opportunity for patients who respond to BH4 to adjust their diet, thereby allowing a greater intake of Phe or even coming off of their Phe-restrictive diet. The overall frequency of BH4 responsiveness across Europe is estimated to be 55-62%, based on projections made using genetic allelic data for BH4 responsiveness, although responsiveness can only be determined by a response test.
The chemical name of sapropterin dihydrochloride is (6R)-2-amino-6-[(1 R,2S)-1 ,2- dihydroxypropyl]-5,6,7,8-tetrahydro-4(1 H)-pteridinone dihydrochloride and the molecular formula is C9H15N5O3 2HCI with a molecular weight of 314.17. Sapropterin dihydrochloride has the following structural formula:
The patent US7727987B2 of Merck discloses crystal forms of (6R)-L-erythro- tetrahydrobiopterin dihydrochloride and hydrates and solvates thereof. Also relates to compositions comprising selected and stable crystal forms of (6R)-L-erythro- tetrahydrobiopterin dihydrochloride or a hydrate thereof and a pharmaceutically acceptable carrier.
The patent EP1757293B1 of Daiichi Sankyo discloses an effective sapropterin hydrochloride preparation that is highly stable during storage and can administer sapropterin hydrochloride, an effective therapeutic agent for the treatment of tetrahydrobiopterin-responsive hyperphenylalaninemia, to patients of a wide range of ages, ranging from infants to adults, in a single preparation.
The patent application EP1845952A2 of BioMarin Pharmaceutical discloses a stable solid formulation of tetrahydrobiopterin, or a precursor or derivative or analog thereof, that maintains its stability for an extended period of time. Compositions of the invention may comprise a stable, crystalline form of BH4 that is stable at room temperature for more than 8 hours and a pharmaceutically acceptable carrier, diluent or excipient. Exemplary stable tablets of the invention have been prepared using a dry tableting process and have been shown to have a shelf-life of at least 6 to 9 months at room temperature. The patent application EP2680848A1 of Dipharma discloses stable pharmaceutical compositions comprising tetrahydrobiopterin and at least one stabilizing agent. Particularly the present invention relates to stable compositions of sapropterin dihydrochloride. Antioxidants that stabilize tetrahydrobiopterin; with the weight ratio of the antioxidant to active ranging from 0.2 - 1.5.
The patent application CN104257623A patent of Guangdong Zhongsheng pharmaceutical company discloses an effervescent tablet containing sapropterin dihydrochloride.
Sapropterin dihydrochloride exhibits polymorphism and many crystalline forms have been identified; among all the polymorphic forms, Form B was identified to be thermodynamically stable crystalline anhydrate form. Polymorph form B is a very stable crystalline form, that can be easily filtered off, dried and ground to particle sizes desired for pharmaceutical formulations. These outstanding properties renders polymorph form B especially feasible for pharmaceutical application.
Sapropterin dihydrochloride is currently available as oral soluble tablets of 100mg and 100mg-500mg powder packets under the brand name Kuvan™. It is marketed by BioMarin in the US and Merck Serono in Europe. Kuvan™ has been designated as an orphan medication since hyperphenylalaninemia is a rare disease. Kuvan™ is indicated to reduce blood phenylalanine levels in patients with hyperphenylalaninemia due to tetrahydrobiopterin responsive phenylketonuria. It is to be used in conjunction with phenylalanine restricted diet. In patients with phenylketonuria the role of sapropterin dihydrochloride is to enable endogenous phenylalanine hydroxylase activity and to partially restore oxidative metabolism of phenylalanine, resulting in decreased blood phenylalanine levels. In patients with BH4 deficiency, sapropterin dihydrochloride is proposed to restore endogenous phenylalanine hydroxylase activity by providing an exogenous source of the missing cofactor.
Tetrahydrobiopterin is an unstable compound; at ambient temperature it is prone to autoxidation in the presence of molecular oxygen. Tetrahydrobiopterin is also very hygroscopic. Therefore, the development of stable oral composition comprising tetrahydrobiopterin that is prone to degradation at room temperature is a challenging task.
Thus, though researchers have developed compositions of sapropterin comprising stabilizers in variety of ratios, the stability of these compositions is low at room temperature or 40°C/75% relative humidity and need to be stored under refrigeration. Low stability of such tetrahydrobiopterin compositions is commercially undesirable and significant degradation due to improper storage could hinder therapy. Need therefore, exists for preparations of tetrahydrobiopterin that are more stable and retain desired amount of active over a longer time even when not refrigerated.
Further, the amount and type of stabilizer and other excipients present in the compositions of sapropterin determine the stability of the active and compositions thereof. Too little or too much stabilizer can affect the stability of the compositions of sapropterin and an appropriate amount of stabilizer must therefore be present in these compositions.
The stable formulations of sapropterin dihydrochloride according to the present invention thus provide desired amount of active over the entire shelf life of the product.
Detailed Description of the Invention
The main object of the present invention is to provide solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutically acceptable excipient with desired stability and bioavailability.
The term "sapropterin dihydrochloride" as used throughout the specification refers to not only sapropterin dihydrochloride, but also its other pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. The amount of sapropterin dihydrochloride is between 15.0-40.0%, preferably 20.0- 30.0%, more preferably 25.0-30.0% by weight of the solid oral pharmaceutical formulation.
In a preferred embodiment according to the present invention, said the solid oral pharmaceutical formulation one or more pharmaceutically acceptable excipient which is selected from antioxidants, binders, disintegrants, lubricants, glidants, diluents or mixtures thereof.
Suitable antioxidants are selected from the group comprising alpha tocopherol (Vitamin E), quercetine, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbyl palmitate, alpha lipoic acid, erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, citric acid, thymol or mixtures thereof. Preferably, antioxidants are selected from quercetine, alpha tocopherol(vitamin E), butylhydroxyanisole or butylhydroxytoluene or mixtures thereof.
The amount of antioxidant is between 5.6-6.4% by weight of the solid oral pharmaceutical formulation.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, corn starch, talc or mixtures thereof.
According to one embodiment of the present invention, the amount of glidant is between 0.1% and 1.0% by weight of the formulation, preferably it is between 0.2% and 1.0% by weight, more preferably it is between 0.5% and 1.0% by weight of the solid oral pharmaceutical formulation.
According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.
Suitable binders are selected from the group comprising lactose anhydrous, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagenselatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
According to one embodiment of the present invention, binders are used to achieve the desired dissolution profile, especially, when the amount of binder is between 1.0% and 50.0%, the solid oral pharmaceutical formulation shows desired dissolution profile.
According to one embodiment of the present invention, the amount of binder is between 1.0% and 50.0%, 5.0% and 50.0%, 10.0% and 50.0%, 20.0% and 50.0% by weight of the solid oral pharmaceutical formulation.
According to one embodiment of the present invention, the binder is lactose anhydrous.
Suitable disintegrants are selected from the group comprising polyvinyl pyrrolidone (crospovidone), crospovidone CL-Superfine (kollidon CL-Superfine), povidone, cross- linked carboxymethyl cellulose (croscarmellose sodium), low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodesyl sulphate, poloxamer, sodium glycine carbonate, sodium lauryl sulphate or mixtures thereof.
According to one embodiment of the present invention, the amount of disintegrant is between 2.0% and 8.0%, 2.0% and 7.0%, 2.0% and 6.0%, 2.0% and 5.0% by weight of the solid oral pharmaceutical formulation. According to one embodiment of the present invention, the disintegrant is sodium starch glycolate.
Suitable lubricants are selected from the group comprising from magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate, sodium lauryl sulphate or mixtures thereof.
According to one embodiment of the present invention, the amount of lubricant is between 0.25% and 5.0%, 0.5% and 4.5%, 1.0% and 4.0%, 2.0% and 3.0% by weight of the solid oral pharmaceutical formulation.
According to one embodiment of the present invention, the lubricant is magnesium stearate.
Suitable diluents which is selected from the group comprising, microcrystalline cellulose, dibasic calcium phosphate, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
According to one embodiment of the present invention, the amount of diluent is between 20.0% and 90.0%, 20.0% and 80.0%, 20.0% and 70.0%, 20.0% and 60.0%, 20.0% and 30.0% by weight of the solid oral pharmaceutical formulation.
According to one embodiment of the present invention, the diluent is microcrystalline cellulose.
According to one embodiment of the present invention, the solid oral pharmaceutical formulation is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solids. Preferably, the solid oral pharmaceutical formulation is in the form of tablets or capsule.
According to an embodiment of the present invention, the solid oral pharmaceutical formulation may be prepared by conventional technology well known to those skilled in the art such as direct compression, dry granulation, wet granulation and the like. During direct compression, active agent and excipients are mixed, sieved and compressed into dosage forms or if the capsule is to be made, powder mixture is filled into gelatin capsules. During wet granulation, the ingredients are mixed and granulated with a granulation liquid. The granulation process provides agglomerates with a desired homogeneity. The mixture is sieved and optionally mixed with additional excipients. Finally, it is compressed into dosage forms or if the capsule is to be made, powder mixture is filled into gelatin capsules. According to another embodiment of the present invention is to provide a stable solid oral pharmaceutical formulation by a simple preparation process. The pharmaceutical formulations of the present invention can be prepared in a fast, efficient, commercially cost low and plant-friendly manufacturing process. A desired dissolution profile of the solid oral pharmaceutical formulation is obtained.
In this present invention, a desired dissolution of the solid oral pharmaceutical formulation is obtained and a desired stability and a simple manufacturing process are in favor of industrial production.
Example 1 : Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression
Process (Direct compression/Capsule filling) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant*, Colloidal silicon dioxide and then adding with geometric dilution method then mixing to obtain a homogenous mixture. b. Adding magnesium stearate to this mixture and mixing them. c.Compressing this mixture into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as antioxidant.
Example 2: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression
Process (Direct compression/ Capsule filling) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant*, Colloidal silicon dioxide and then adding with geometric dilution method then mixing to obtain a homogenous mixture. b. Adding magnesium stearate to this mixture and mixing them. c.Compressing this mixture into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant. Example 3: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression Process (Direct compression/ Capsule filling) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous,
Microcrystalline cellulose, Antioxidant*, Colloidal silicon dioxide and then adding with geometric dilution method then mixing to obtain a homogenous mixture. b. Adding magnesium stearate to this mixture and mixing them. c. Compressing this mixture into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
Example 4: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with direct compression Process (Direct compression/Capsule filling) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant*, Colloidal silicon dioxide and then adding with geometric dilution method then mixing to obtain a homogenous mixture. b. Adding magnesium stearate to this mixture and mixing them. c.Compressing this mixture into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
Example 5: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation **q.s.: quantity sufficient
Process (Wet granulation) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant* and water is added then mixing to obtain a homogenous mixture, colloidal silicon dioxide is added after it is also sieved and mixed. Then magnesium stearate is added to this powder mixture and mixed. b. Finally the powder mixture is compressed into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.
Example 6: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
**q.s.: quantity sufficient Process (Wet granulation) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant* and water is added then mixing to obtain a homogenous mixture, colloidal silicon dioxide is added after it is also sieved and mixed. Then magnesium stearate is added to this powder mixture and mixed. b. Finally the powder mixture is compressed into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant. Example 7: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
**q.s.: quantity sufficient
Process (Wet granulation) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant* and water is added then mixing to obtain a homogenous mixture, colloidal silicon dioxide is added after it is also sieved and mixed. Then magnesium stearate is added to this powder mixture and mixed. b. Finally the powder mixture is compressed into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant. Example 8: Sapropterin dihydrochloride and at least one pharmaceutical excipient processed with wet granulation
**q.s.: quantity sufficient
Process (Wet granulation) a. Sieving Sapropterin dihydrochloride, Sodium starch glycolate, Lactose anhydrous, Microcrystalline cellulose, Antioxidant* and water is added then mixing to obtain a homogenous mixture, colloidal silicon dioxide is added after it is also sieved and mixed. Then magnesium stearate is added to this powder mixture and mixed. b. Finally the powder mixture is compressed into tablets or if the capsule is to be made, powder mixture is filled into gelatin capsules.
* Butylhydroxyanisole, Butylhydroxytoluene, vitamin E, Quercetine or Citric acid can be used as an antioxidant.

Claims

1. A solid oral pharmaceutical formulation comprising sapropterin dihydrochloride and at least one pharmaceutically acceptable excipient, wherein sapropterin dihydrochloride is present in an amount of 15.0% to 40.0% by weight of the total formulation.
2. The solid oral pharmaceutical formulation according to claim 1 , wherein sapropterin dihydrochloride is present in an amount of preferably 20 to 35 %, more preferably 25.0% to 30.0% by weight of the total formulation.
3. The solid oral pharmaceutical formulation according to claim 1 , wherein at least one pharmaceutically acceptable excipient is selected from the group comprising antioxidants, lubricants, glidants, diluents, binders, disintegrants.
4. The solid oral pharmaceutical formulation according to claim 3 wherein the amount of antioxidant is between 5.6% and 6.4% by weight of the total formulation.
5. The solid oral pharmaceutical formulation according to claim 3, wherein antioxidants are selected from the group comprising alpha tocopherol (Vitamin E), quercetine ascorbyl palmitate, alpha lipoic acid, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, citric acid, thymol or mixtures thereof.
6. The solid oral pharmaceutical formulation according to claim 5, wherein the antioxidant is preferably selected from quercetine, alpha tocopherol (vitamin E), butylhydroxyanisole, butylhydroxytoluene, citric acid or mixtures thereof.
7. The solid oral pharmaceutical formulation according to claim 3, wherein binders are selected from the group comprising polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, lactose anhydrous, sodium alginate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagenselatin, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminium hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
8. The solid oral pharmaceutical formulation according to claim 7, wherein the amount of binder is between 1.0% and 50.0% by weight of the total formulation.
9. The solid oral pharmaceutical formulation according to any preceding claims wherein the dosage form of the formulation is in the form of tablets, capsules, strips, powders, pastilles, sachets, effervescent compositions, pills, coated bead systems, granules, microspheres, dragees, films or orally administrable films.
10. The solid oral pharmaceutical formulation according to 9, wherein the solid oral pharmaceutical formulation is in the form of tablet or capsule.
11. The solid oral pharmaceutical formulation according to claim 10, wherein tablet or capsule comprising;
25.0 - 30.0 % by weight of sapropterin dihydrochloride 2.0 - 8.0% by weight of sodium starch glycolate 1.0 - 50.0% by weight of lactose anhydrous 20.0-90.0 % by weight of microcrystalline cellulose
5.6-6.4%by weight of quercetine, vitamin E, butylhydroxyanisole butylhydroxytoluene or citric acid
0.10-1.0 % by weight of colloidal silicon dioxide
0.25-5.0% by weight of magnesium stearate
12. The solid oral pharmaceutical formulation according to claim 10, wherein tablet or capsule comprising;
28.0 % by weight of sapropterin dihydrochloride
4.0 % by weight of sodium starch glycolate 30.0% by weight of lactose anhydrous 28.5% by weight of microcrystalline cellulose 6.0% by weight of quercetine, vitamin E, butylhydroxyanisole butylhydroxytoluene or citric acid 1.0% by weight of colloidal silicon dioxide 2.5% by weight of magnesium stearate
13. The solid oral pharmaceutical formulation according to any preceding claims, wherein the pharmaceutical formulation is prepared by using direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, slugging, spray drying or solvent evaporation.
EP20868515.6A 2019-09-23 2020-08-05 Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient Pending EP4034120A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/14406A TR201914406A2 (en) 2019-09-23 2019-09-23 SOLID ORAL PHARMACEUTICAL FORMULATIONS CONTAINING SAPROPTERIN DIHYDROCHLORIDE AND AT LEAST ONE PHARMACEUTICAL EXCIPIENT
PCT/TR2020/050688 WO2021061065A1 (en) 2019-09-23 2020-08-05 Solid oral pharmaceutical formulations comprising sapropterin dihydrochloride and at least one pharmaceutical excipient

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