HK1121950B - Stable pharmaceutical composition comprising a pyrimidine-sulfamide - Google Patents

Description

Stable pharmaceutical compositions comprising pyrimidine-sulfonamides

Field of the invention

The present invention relates to stable pharmaceutical compositions comprising propylaminesulfonic acid [5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl ] -amide or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, the compound being hereinafter referred to as the compound of formula I. The compounds of formula I have the formula:

background

The compounds of formula I are endothelin receptor inhibitors and are useful as endothelin receptor antagonists. Compounds of formula I and their preparation are disclosed in WO 02/053557.

Disclosure of Invention

In the context of the present disclosure, any reference to a compound of formula I is to be understood as referring also to pharmaceutically acceptable salts or solvates (including hydrates) of the compound of formula I, and morphological forms thereof, if not otherwise indicated and where appropriate and reasonable.

The compounds of formula I of the present invention are currently being evaluated in clinical trials and it is therefore necessary to develop a stable formulation. The present invention thus relates to a stable pharmaceutical composition comprising the compound propylamidosulfonic acid [5- (4-bromo-phenyl) -6- [2- (5-bromo-pyrimidin-2-yloxy) -ethoxy ] -pyrimidin-4-yl ] -amide or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof.

A stable pharmaceutical composition according to the invention will comprise:

a) a compound of formula I having the formula shown below, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof;

b) a filler;

c) a decomposition agent;

d) a surfactant;

e) and (3) a lubricant.

According to a preferred embodiment of the invention, the pharmaceutical composition will be in the form of a tablet.

According to another preferred embodiment of the invention, the pharmaceutical composition will be in the form of a capsule.

The stable pharmaceutical composition according to the invention will preferably result in a bulking agent selected from one or more of the following: lactose, corn starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO)₄·2H₂O), microcrystalline cellulose, maltodextrin, and mannitol; the decomposer is selected from one or more of the following substances: croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, crospovidone, polyvinylpyrrolidone, alginic acid, sodium alginate, pregelatinized starch, guar gum, clay, and ion exchange resin; the surfactant is selected from the following substances: sodium lauryl sulfate, polysorbate, polyethylene polyoxypropylene polymer, polyoxyethylene stearate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene C_1-4-alkyl ethers, sucrose monoesters and lanolin and ethers; and the lubricant is selected from the following: magnesium stearate, aluminum stearate or calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, fatty acid monoglyceride, polyethylene glycol, hydrogenated cottonseed oil, castor seed oil, and sucrose ester.

The stable pharmaceutical composition according to the invention may comprise, inter alia:

a) a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or morphic form thereof;

b) one or more excipients selected from the group consisting of lactose, corn starch, pregelatinized starch, calcium hydrogen phosphate, and microcrystalline cellulose;

c) polyvinylpyrrolidone;

d) sodium starch glycolate;

e) a surfactant; and

f) and (3) a lubricant.

The stable pharmaceutical composition according to the invention may more particularly comprise:

a) a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, in a total amount of up to 50% by weight (for example in an amount of 1 to 50% by weight, in particular in an amount of 5 to 30% by weight and especially in an amount of 10 to 20% by weight), based on the total weight of the pharmaceutical composition;

b) one or more excipients selected from the group consisting of lactose, corn starch, pregelatinized starch, calcium hydrogen phosphate and microcrystalline cellulose, in a total amount of 10 to 95% by weight based on the total weight of the pharmaceutical composition (e.g., in an amount of 30 to 90% by weight, particularly in an amount of 50 to 80% by weight, and especially in an amount of 60 to 75% by weight based on the total weight of the pharmaceutical composition);

c) polyvinylpyrrolidone in a total amount of up to 20 wt% (e.g., in an amount of 0.5 to 10 wt%, particularly in an amount of 1 to 5 wt%, and especially in an amount of 2 to 4 wt%), based on the total weight of the pharmaceutical composition;

d) sodium starch glycolate in a total amount up to 30 wt% (e.g., in an amount of 0.5 to 20 wt%, particularly in an amount of 1 to 10 wt%, and especially in an amount of 2 to 6 wt%), based on the total weight of the pharmaceutical composition;

e) a surfactant in a total amount of up to 7 wt% (e.g., in an amount of 0.01 to 5 wt%, particularly in an amount of 0.05 to 1 wt%, and especially in an amount of 0.1 to 0.5 wt%), based on the total weight of the pharmaceutical composition; and

f) a lubricant in a total amount of up to 10 wt. -%, based on the total weight of the pharmaceutical composition (e.g. in an amount of 0.05 to 5 wt. -%, in particular in an amount of 0.1 to 2 wt. -%, and especially in an amount of 0.25 to 1.5 wt. -%, based on the total weight of the pharmaceutical composition).

For example, a stable pharmaceutical composition according to the invention may comprise:

a) a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, in a total amount of up to 50% by weight (for example in an amount of 1 to 50% by weight, in particular in an amount of 5 to 30% by weight and especially in an amount of 10 to 20% by weight), based on the total weight of the pharmaceutical composition;

b) lactose or lactose monohydrate in a total amount of 10 to 75 wt. -%, based on the total weight of the pharmaceutical composition (e.g. in an amount of 30 to 70 wt. -%, in particular in an amount of 45 to 65 wt. -%, and especially in an amount of 52 to 60 wt. -%, based on the total weight of the pharmaceutical composition);

c) microcrystalline cellulose in a total amount of 0 to 20 wt% (e.g., in an amount of 1 to 10 wt%, particularly in an amount of 2 to 8 wt%, and especially in an amount of 4 to 6 wt%), based on the total weight of the pharmaceutical composition;

d) polyvinylpyrrolidone in a total amount of up to 20 wt% (e.g., in an amount of 0.5 to 10 wt%, particularly in an amount of 1 to 5 wt%, and especially in an amount of 2 to 4 wt%), based on the total weight of the pharmaceutical composition;

e) sodium starch glycolate in a total amount up to 30 wt% (e.g., in an amount of 0.5 to 20 wt%, particularly in an amount of 1 to 10 wt%, and especially in an amount of 2 to 6 wt%), based on the total weight of the pharmaceutical composition;

f) a surfactant in a total amount of up to 7 wt% (e.g., in an amount of 0.01 to 5 wt%, particularly in an amount of 0.05 to 1 wt%, and especially in an amount of 0.1 to 0.5 wt%), based on the total weight of the pharmaceutical composition; and

g) a lubricant in a total amount of up to 10 wt. -%, based on the total weight of the pharmaceutical composition (e.g. in an amount of 0.05 to 5 wt. -%, in particular in an amount of 0.1 to 2 wt. -%, and especially in an amount of 0.25 to 1.5 wt. -%, based on the total weight of the pharmaceutical composition).

The pharmaceutical composition according to the invention may in particular comprise:

a) a compound of formula I according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate or morphic form thereof;

b) lactose or lactose monohydrate;

c) microcrystalline cellulose;

d) polyvinylpyrrolidone;

e) sodium starch glycolate;

f) a surfactant; and

g) and (3) a lubricant.

According to a preferred embodiment of the above composition, the surfactant is polysorbate.

According to another preferred embodiment of the above composition, the lubricant is magnesium stearate.

The stable pharmaceutical compositions of the present invention may also optionally include a slip agent. The present invention therefore further provides a stable pharmaceutical composition comprising:

a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof;

b) a filler;

c) a decomposition agent;

d) a surfactant;

e) a slip agent; and

f) and (3) a lubricant.

Fillers according to the present invention include, but are not limited to, one or more of the following: lactose, corn starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO)₄·2H₂O), microcrystalline cellulose, maltodextrin, and mannitol. Preferably, lactose is used with microcrystalline cellulose, lactose is used with corn starch, pregelatinized starch is used with microcrystalline cellulose, or dibasic calcium phosphate dihydrate is used with microcrystalline cellulose. Lactose monohydrate (e.g. Pharmatose)200Mesh) with microcrystalline cellulose (e.g. Avicel)PH101) are also preferred.

The decomposing agent according to the present invention includes (but is not limited to) one or more of the following: croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crospovidone (e.g., crospovidone (PVP XL, povidone available from ISP company, or Kollidon from BASF)XL)), polyvinylpyrrolidone (PVP), alginic acid, sodium alginate, pregelatinized starch, guar gum, clay, and ion exchange resins. Sodium starch glycolate or a combination of sodium starch glycolate and PVP is preferably used as the disintegrant.

Surfactants according to the present invention include, but are not limited to, one or more of the following: sodium dodecyl sulfate, polysorbate (Tween)Commercially available), polyethylene polyoxypropylene polymer (Pluronic F65), polyoxyethylene stearate (MYRJ), dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters (commercially available)From Nikko Chemicals), polyethylene oxide C_1-4Alkyl ethers, sucrose monoesters and lanolin and ethers. Sodium lauryl sulfate is preferably used as the surfactant.

The polysorbate included in the composition according to the present invention will have an average degree of polymerization of 20 to 100 (preferably about 80) monomer units, and may be, for example, polysorbate 80. Preferably, the polysorbate should also be derived from plants.

Slip agents according to the present invention include, but are not limited to, one or more of the following: silica, colloidal silicon dioxide (e.g. anhydrous silica gel (e.g. Aerosil)200) Magnesium trisilicate, powdered cellulose, starch, and talc. Colloidal silica is preferably used.

Lubricants according to the present invention include (but are not limited to) one or more of the following: magnesium, aluminum or calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, monoglyceride of fatty acids (e.g. from Danisco, UK) having a molecular weight of from 200 to 800 daltons, for example, glyceryl monostearate (e.g. from Danisco, UK), glyceryl dibehenate (e.g. compritol at 0888)^TMGattefosse France), palm-based glyceryl stearate (e.g. Precirol^TMGattefosse France), polyethylene glycol (PEG, BASF), hydrogenated cottonseed oil (Lubitab, Edward Mendell Co Inc.), castor seed oil (Cutina HR, Henkel), and sucrose esters (surfhoe SE, Mitsubishi-Kagaku FoodsCo). Magnesium stearate is preferably used.

It is understood that any given excipient may serve multiple functions, such as acting as a filler, disintegrant, surfactant, glidant, and/or lubricant.

The stable pharmaceutical compositions of the present invention (whether or not a slip agent is included) may optionally also include tartaric acid.

Lactose commercially available from commercial suppliers is used in the present invention, preferably lactose monohydrate (such as from lactose monohydrate)Pharmatose of DMV International200M) are used in the present invention.

Corn starch from commercial suppliers is used in the present invention, preferably corn starch from Roquette.

Pregelatinized starch, available from commercial suppliers, is used in the present invention, preferably starch 1500 (from Colorcon) is used in the present invention.

Dibasic calcium phosphate dihydrate is commercially available from commercial suppliers and is preferably used in the present invention in an unground form, such as Caliphar A or A-Tab.

Microcrystalline cellulose, available from commercial suppliers, was used in the present invention, and Avicel PH101 from FMC International was used in the present invention.

Polyvinylpyrrolidone (PVP) available from commercial suppliers is used in the present invention, preferably polyvinylpyrrolidone from BASF.

Sodium starch glycolate, commercially available from commercial suppliers, is used in the present invention, preferably sodium starch glycolate from Roquette.

Sodium lauryl sulfate, commercially available from commercial suppliers, is preferably used in the present invention, sodium lauryl sulfate from Ellis & Everard is preferably used in the present invention.

Colloidal silica is commercially available from commercial suppliers for use in the present invention, preferably Aerosil from Degussa AG is used in the present invention.

Magnesium stearate from commercial suppliers is used in the present invention, preferably magnesium stearate from Peter Greven.

The term "C" alone or in combination with other groups_1-4-alkyl "means a straight or branched chain alkyl group having 1 to 4 carbon atoms. Straight or branched C₁-C₄Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, second butyl, isobutyl, third butyl.

In the present application, the term "about" preceding the value "X" refers to the interval extending from X minus 10% X to X plus 10% X, and preferably to the interval extending from X minus 5% X to X plus 5% X.

The expression pharmaceutically acceptable salts encompasses salts of inorganic or organic acids such as hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are not toxic to living organisms, or salts of inorganic bases such as alkali or alkaline earth bases, for example sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, when the compounds of formula I are acidic in nature.

The expression ww% refers to the weight percentage compared to the total weight of the composition considered.

In a preferred embodiment of the present invention, the pharmaceutical composition comprises:

a filler selected from one or more of the following: lactose, corn starch, pregelatinized starch, dibasic calcium phosphate dihydrate (CaHPO)₄·2H₂O) and microcrystalline cellulose, maltodextrin and mannitol; a disintegrant selected from one or more of the following: croscarmellose sodium, sodium starch glycolate, CMC-Ca, CMC-Na, crosslinked PVP, alginic acid, sodium alginate, pregelatinized starch, guar gum, clay and ion exchange resin; a surfactant selected from the group consisting of: sodium lauryl sulfate, polysorbate, polyethylene polyoxypropylene polymer, polyoxyethylene stearate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene C_1-4-alkyl ethers, sucrose monoesters and lanolin and ethers; a slip agent selected from the group consisting of: silicon dioxide, silica gel, magnesium trisilicate, powdered cellulose, starch and talc; lubrication selected fromPreparation: magnesium stearate, aluminum stearate or calcium stearate, stearic acid, sodium stearyl fumarate, talc, sodium benzoate, fatty acid monoglyceride, polyethylene glycol, hydrogenated cottonseed oil, castor seed oil, and sucrose ester.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises:

a) a mixture of at least one or more of the following excipients selected from lactose, corn starch, pregelatinized starch, dibasic calcium phosphate and microcrystalline cellulose;

b) polyvinylpyrrolidone;

c) sodium starch glycolate;

d) sodium lauryl sulfate;

e) colloidal silicon dioxide; and

f) magnesium stearate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises:

a) a mixture of at least one or more of the following excipients selected from lactose, corn starch, starch 1500, calicharm a and Avicel PH 101;

b) polyvinylpyrrolidone;

c) sodium starch glycolate;

d) sodium lauryl sulfate;

e) aerosil; and

f) magnesium stearate.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises:

a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, in a total amount up to 50% by weight, based on the total weight of the pharmaceutical composition;

b) a mixture of at least one or more fillers in a total amount of 10 to 95% by weight, based on the total weight of the pharmaceutical composition;

c) polyvinylpyrrolidone in a total amount of up to 20% by weight based on the total weight of the pharmaceutical composition;

d) sodium starch glycolate in a total amount up to 30 weight percent based on the total weight of the pharmaceutical composition;

e) a surfactant in a total amount of up to 7% by weight based on the total weight of the pharmaceutical composition;

f) a slip agent in a total amount of up to 5% by weight based on the total weight of the pharmaceutical composition; and

g) a lubricant in a total amount of up to 10% by weight based on the total weight of the pharmaceutical composition; whereby the total w% of the pharmaceutical composition is 100.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises:

a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, in a total amount up to 50% by weight, based on the total weight of the pharmaceutical composition;

b) a mixture of at least one or more fillers in a total amount of up to 30 to 85% by weight based on the total weight of the pharmaceutical composition;

c) polyvinylpyrrolidone in a total amount ranging from 2 to 10% by weight based on the total weight of the pharmaceutical composition;

d) sodium starch glycolate in a total amount up to 10 weight percent based on the total weight of the pharmaceutical composition;

e) a surfactant in a total amount of up to 3% by weight based on the total weight of the pharmaceutical composition;

f) a slip agent in a total amount of up to 2.5% by weight based on the total weight of the pharmaceutical composition; and

g) a lubricant in a total amount of up to 7% by weight based on the total weight of the pharmaceutical composition; whereby the total w% of the pharmaceutical composition is 100.

In another preferred embodiment of the present invention, the pharmaceutical composition comprises:

a) a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof, in a total amount up to 50% by weight, based on the total weight of the pharmaceutical composition;

b) a mixture of at least one or more fillers in a total amount of 30 to 85% by weight based on the total weight of the pharmaceutical composition,

c) polyvinylpyrrolidone in a total amount ranging from 2 to 5% by weight based on the total weight of the pharmaceutical composition;

d) sodium starch glycolate in a total amount up to 5% by weight based on the total weight of the pharmaceutical composition;

e) a surfactant in a total amount of up to 3% by weight based on the total weight of the pharmaceutical composition;

f) a slip agent in a total amount of up to 1% by weight based on the total weight of the pharmaceutical composition; and

g) a lubricant in a total amount of up to 3% by weight based on the total weight of the pharmaceutical composition; whereby the total w% of the pharmaceutical composition is 100.

The pharmaceutical composition according to the invention or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof can be used as a medicament.

The pharmaceutical composition according to the invention or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof can be used for the preparation of a medicament for the treatment of Pulmonary Arterial Hypertension (PAH).

Reference is made to the extensive references on these or other pharmaceutically acceptable excipients and the subject matter of the procedures described herein, see in particular: handbook of Pharmaceutical Excipients, third edition, edited by Arthur H.Kibbe, American Pharmaceutical Association, Washington, USA, and Pharmaceutical Press, London; and Lexikon der Hilfstdefurf ü r Pharmazie, Kosmetik und angrenzende Gebiete, ed.P.Fiedler, fourth edition, Edito Cantor, Aulendorf and earlier versions.

According to the present invention, the amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate or morphic form thereof may be a total amount of up to 90% by weight, based on the total weight of the pharmaceutical composition. The amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof may preferably be a total amount of up to 50% by weight, based on the total weight of the pharmaceutical composition. The amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof will more preferably be from 1 to 50% by weight, in particular from 5 to 30% by weight and especially from 10 to 20% by weight, based on the total weight of the pharmaceutical composition.

According to the present invention, the amount of filler may vary from 10 to 95 wt. -%, in particular from 30 to 85 wt. -%, and more in particular from 30 to 50 wt. -%, based on the total weight of the pharmaceutical composition.

The amount of disintegrant may vary from 1 to 20 wt%, preferably from 2 to 10 wt% (e.g. 3 to 8 wt%), and especially from 2 to 5 wt%, based on the total weight of the pharmaceutical composition. For example, the composition may comprise 2 to 4 weight percent (e.g., 3 weight percent) of the disintegrant, based on the total weight of the pharmaceutical composition.

The amount of surfactant may vary from 0.01 to 7% by weight, preferably from 0.1 to 3% by weight, and especially from 0.1 to 1% by weight, based on the total weight of the pharmaceutical composition.

When present in the composition, the amount of the slip agent may vary from 0.1 to 5 wt. -%, particularly from 0.1 to 2.5 wt. -%, particularly from 0.5 to 1.0 wt. -%, based on the total weight of the pharmaceutical composition.

The amount of lubricant may vary between 0.05 and 10 wt. -%, preferably between 0.05 and 7 wt. -%, most preferably between 0.1 and 3.0 wt. -% and in particular between 0.1 and 1 wt. -%, based on the total weight of the pharmaceutical composition.

When present in the composition, the amount of tartaric acid can vary from 0.1 to 10 wt.%, preferably from 1 to 10 wt.%, and most preferably from 4 to 6 wt.%, based on the total weight of the pharmaceutical composition.

The absolute amount of each pharmaceutically acceptable excipient and the amount relative to the other pharmaceutically acceptable excipients depends on the desired properties of the tablet and can be selected by routine experimentation.

The total weight percentage of the pharmaceutical composition is 100.

A pharmaceutical composition according to the invention is considered "stable" if an initial content of 70%, preferably 80% and most preferably 95% of the compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate or form thereof is preserved over a period of time.

The stability of the pharmaceutical compositions can be tested in a conventional manner, for example by measuring the compounds of formula I and their degradation products, dissolution, friability, disintegration time, appearance and/or microscopy, after storage at 25 ℃ and 60% relative humidity for a defined period of time and/or after storage at 40 ℃ and 75% relative humidity for a defined period of time.

Examples of dissolution testing procedures are given in the experimental section following the examples.

Preferably, the solid composition of the invention will be stable for at least 6 or 12 months when stored at a temperature of 5 to 50 ℃. More preferably, it will be stable for at least 6 or 12 months when stored at a temperature of 15 to 45 ℃. Optimally, it will be stable for at least 6 or 12 months when stored at a temperature of 25 to 40 ℃.

In a more preferred embodiment, the pharmaceutical composition is stable for a certain period of time, such as 1 year and preferably 2 years. The pharmaceutical composition is more stable for 3 years.

The content of compound 1 and its degradation products in the capsules or tablets was evaluated by HPLC.

The pharmaceutical composition can be formulated into capsule and tablet. For example, a 1mg dose concentration of 1625g (6500 capsules) batch size may be prepared as follows:

						material (chemical name)		Function(s)	Percentage of formulation (% w/w)	Unit dose (mg)	For 6500 capsules (g)
Inside grain	A compound of formula I	Active agent	0.40	1.00	6.5
						Pregelatinized corn starch, EP/BP/NF	Diluent	73.30	183.25	1191.125
	Microcrystalline fibrePlain, EP	Diluent/decomposer	10.00	25.00	162.500
						Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	32.500
	Sodium dodecyl sulfate, EP/NF	Surface active agent	1.00	2.50	16.250

Extragranular	Microcrystalline cellulose, EP	Diluent/decomposer	10.00	25.00	162.500
						Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	32.500
	Colloidal silica, EP/NF	Sliding agent	0.30	0.75	4.875
						Magnesium stearate, EP/BP	Lubricant agent	1.00	2.50	16.250
	Total of			100.000	250.00						1625.00

The intragranular material is pre-mixed for 5 minutes in a high shear mixer such as Diosna (6L wrist cavity). While mixing, about 731 to 893g of water was added to the intragranular material at a rate of 65 grams per minute until appropriate granules were formed. The intragranular material was mixed for two more minutes. It is then dried in a fluid bed dryer at an inlet air temperature of 60 ℃ until the weight loss of the particles on drying is 6 to 9% w/w. The pellets were then passed through a granulator equipped with a 813 μm sieve. All extragranular materials except magnesium stearate were passed through a 1000 μm sieve and mixed with the pellets in a 10L Pharmatech double cone mixer at 25rpm for 25 minutes. The magnesium stearate was sieved through a 500 μm sieve and added to the remaining powder mixture in the mixer and mixed for an additional 3 minutes.

The powder was then filled into "0" sized white opaque hard gelatin capsules.

In one aspect of the invention, one or more lubricants may be sprayed on the material in contact with the surface of the pressing tool, e.g. punch and/or die, of the ingot-making machine prior to compression.

The capsules may vary in size, for example, from 1 to "00" in size.

According to the invention, tablets may also be prepared. The tablets may differ in shape and be, for example, circular, oval, rectangular, cylindrical, clover-shaped, or any other suitable shape.

In one embodiment of the invention, the resulting tablet is clover-shaped or round. The edge of the tablet may be beveled or rounded. In another embodiment, the tablet is clover-shaped with beveled edges. The tablets according to the invention may be scored or engraved.

The tablets according to the invention may also be clover-leaf-shaped in four equal parts with beveled edges. It may have a diameter in the range between 5 and 15mm (e.g. a diameter of 5 to 8mm such as a 6mm diameter), in particular in the range between 8 and 15mm, and in particular in the range between 9 and 11 mm. Its thickness (before coating, if a coating film is applied to the tablet, the thickness before coating) is in the range of 2.5 to 4.5mm, preferably between 2.9 and 3.9 mm.

The capsules and tablets of the invention may be dyed and/or marked to impart a separate appearance and make them immediately identifiable. The use of dyes can be used to enhance appearance and identification of the tablet. Dyes suitable for use in pharmaceuticals typically include carotenoids, iron oxides or chlorophyll. The tablets of the invention may be marked using an embossed code.

The capsules and tablets of the invention are suitable for the treatment of PAH and show a good pharmacokinetic profile.

Procedures that may be used may be conventional or known in The art or based on, for example, The procedures described in l.lachman et al, The Theory and Practice of industrial Pharmacy, third edition, 1986; sucker et al, Pharmazeutische technology, Thieme, 1991; these procedures in Hagers handbuch der pharmazeutischen Praxis, fourth edition (Springer Verlag, 1971) and Remington's Pharmaceutical Sciences, 13 th edition, (Mack Publ., Co., 1970) or later versions.

The process according to the invention for preparing a pharmaceutical composition in capsule form can be carried out according to the following process scheme:

the drying step can be carried out in particular using a fluidized bed dryer.

When the pharmaceutical composition to be prepared is in the form of tablets, the preparation process according to the invention can be carried out according to the following process scheme:

two variations of the process can be performed, one involving wet granulation (i.e. a process as shown in the above-mentioned flow sheet wherein some water is added to the intragranular material and water is removed by a drying step) and the other involving direct compression (i.e. a process as shown in the above-mentioned flow sheet wherein the drying step is omitted, which is superfluous since no water is added to the intragranular material).

According to a preferred variant of the process, the tablets obtained by the preparation process previously stated are coated with a protective film. The protective film will in particular prevent direct contact of the tablet with moisture, which may also alleviate imprint in the tablet.

According to the invention, the amount of coating substance will be from 2 to 8% by weight, preferably from 3 to 7% by weight and more preferably from 4 to 6% by weight of the tablet before coating.

The coating material from which the protective film is made will include a low water vapor permeability polymer such as polyvinyl alcohol (e.g., Opadry)AMB) or dimethylaminoethyl methacrylate (e.g. Eudragit)E PO)). The coating material may further include a plasticizer (e.g., propylene glycol, triacetine, dibutyl phthalate or dibutyl sebacate), a surfactant (e.g., sodium lauryl sulfate or a polysorbate, such as Tween), and/or a lubricant/slip agent (e.g., stearic acid, magnesium or calcium stearate or talc). In addition, the coating material may also include pigments (e.g., iron (II) oxide, iron (III) oxide or titanium oxide) to impart a colored appearance to the tablet.

Detailed description of the preferred embodiments

The following non-limiting examples illustrate the invention.

Examples of the invention

The pharmaceutical compositions of examples 1-15 were prepared according to the method summarized by the following scheme.

The pharmaceutical compositions of examples 16-33 were prepared following the wet granulation process summarized by the following flow chart.

Finally, the pharmaceutical compositions of examples 34-35 were prepared by following the direct compression method summarized by the following flow chart.

(Note: in the above-described flow charts, RPM means revolutions per minute)

For using OpadryThe tablet coating process for AMB coating uses the following detailed procedure (hereinafter referred to as "with OpadryMonolithic coating method of AMB coating).

Preparation of 20% w/w Opadry in purified water at room temperature in a stainless steel vesselAMB (Fine white powder) Dispersion to obtain OpadryCoating solution for AMB coated tablets. The dispersion was stirred for 45 minutes with a Heidolph stirrer with stirring paddles before use and throughout the stirring. The coating pan (pan) may be allowed to equilibrate to the set point temperature (60 ℃) before filling with tablets. Tablets, when applied prior to coating, may be equilibrated in a dry pan for 10 minutes. The same temperatures and air flows are used during the heating, coating and drying stages.

The coating of tablets containing the compound of formula I uses the following parameters:

coating Pan (Coating Pan)	Accelacota 24' with Manesty Flowtab device "
		Inlet temperature	60℃
Exhaust temperature	40℃
		Drum Speed (Drum Speed)	12-14RPM
Spray Rate (Spray Rate)	After 60min of spraying, 10g/min was increased to 15g/min
		Fluid nozzle (mm)	1.2mm

Spray gun (Spray gun)	Manesty MK-2
		Atomizing Air Pressure (atomization Air Pressure)	50psi
Fan Width Air Pressure (Fan Width Air Pressure)	50psi
		Weight (g) of model tablet for stacking out tablet layer (Weight of dummy to bulk out of the tabletted)	7000
Weight (g) of active tablets (Weight of active tablets)	300
		Active tablet number (No. of active tablets)	4300
Total weight of tablet layer g) (Total weight of tablet bed)	7300

The air flow in the coating pan was not measured at the time of coating, but was subsequently started to measure and was found to be about 250m per hour³. The film coating was completed between 110 minutes and 120 minutes (the coating was stopped when 1460g of solution was sprayed). After coating, the tablets were dried in a pan for 10 minutes.

About the use of EUDRAGITThe method of coating the tablets with E PO coating uses the following detailed procedure (hereinafter referred to as "with EUDRAGITOne-piece application method of E PO coating).

At a LThe coating test was completed in dige LHC 25. The lance type was an unloaded lance with a spray nozzle of 1.2mm diameter Schlick 970/7-1S 75. A Verder CD70 peristaltic pump and a 2mm inner diameter silicon tube were used as the delivery system for the spray suspension.

Obtaining for EUDRAGITThe coating suspension of the E PO coated tablets is as follows:

in a vessel containing a given amount of water, the corresponding amount of sodium lauryl sulfate was added and the mixture was homogenized for 5 minutes with an ULTRA turrax. Thereafter, a small amount of stearic acid of the corresponding amount is added and homogenized for 5-10 minutes. After the homogenization period, EUDRAGIT was slowly added in small amountsE PO and homogenize for 30 min. Then, a corresponding amount of magnesium stearate was prepared as a 15% suspension in water using ULTRA Turrax. Adding the magnesium stearate suspension to EUDRAGITE PO solution. The suspension was continuously stirred during the process using a conventional propeller stirrer.

Example 1

Batch size: 20g of

Material	％w/w
		A compound of formula I	40.0
Medicinal lactose DCL11	28.7
		Starch 1500	25.0
Sodium starch glycolate	4.0
		Sodium dodecyl sulfate	1.0
Colloidal silica	0.3
		Magnesium stearate	1.0
Total of	100.0

Examples 2 and 3

Batch size: 625g

Material	Example 2	Example 3
			A compound of formula I	0.08	0.08
Medicinal lactose DCL11	68.62	-
			Starch 1500	-	93.62
Avicel PH101	25.00	-
			Sodium starch glycolate	4.00	4.00
Sodium dodecyl sulfate	1.00	1.00
			Aerosil 200	0.30	0.30
Magnesium stearate	1.00	1.00

Material	Example 2	Example 3
				100	100

Examples 4 to 11

Intragranular material										Extragranular material
														% w/w of a compound of formula I	％w/w Pharmatose200M	% w/w corn starch	% w/w corn starch 1500	％w/w Calipharm A	％w/w Avicel PH101	% w/w polyvinylpyrrolidone	% w/w sodium starch glycolate	% w/w sodium dodecyl sulfate		％w/w Avicel PH101	% w/w sodium starch glycolate	％w/w Aerosil 200	% w/w magnesium stearate
0.08	70.62	-	-	-	10.00	3.00	2.00	1.00		10.00	2.00	0.30	1.00
														0.08	-	-	73.62	-	10.00	-	2.00	1.00		10.00	2.00	0.30	1.00
40.00	30.70	-	-	-	10.00	3.00	2.00	1.00		10.00	2.00	0.30	1.00
														40.00	-	-	33.70	-	10.00	-	2.00	1.00		10.00	2.00	0.30	1.00
0.40	70.30	-	-	-	10.00	3.00	2.00	1.00		10.00	2.00	0.30	1.00
														0.40	-	-	73.30	-	10.00	-	2.00	1.00		10.00	2.00	0.30	1.00
0.08	70.62	20.00	-	-	-	3.00	2.00	1.00		-	2.00	0.30	1.00
														0.08	-	-	-	70.62	10.00	3.00	2.00	1.00		10.00	2.00	0.30	1.00

Example 12

Compound of formula I capsule 0.2mg
						Material (chemical name)		Function(s)	Percentage of formulation (% w/w)	Unit dose (mg)	Typical batch size (g)

Compound of formula I capsule 0.2mg
						Inside grain	A compound of formula I	Active agent	0.08	0.20	0.600
Pregelatinized corn starch, EP/BP/NF	Diluent	73.62	184.05	552.15
					Microcrystalline cellulose, EP		Diluent/decomposer	10.00	25.00	75.00
Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
					Sodium dodecyl sulfate, EP/NF		Surface active agent	1.00	2.50	7.50
Extragranular	Microcrystalline cellulose, EP	Diluent/decomposer	10.00	25.00							75.00
					Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
	Colloidal silica, EP/NF	Sliding agent	0.30	0.75						2.25
					Magnesium stearate, EP/BP	Lubricant agent	1.00	2.50	7.50
	Total of			100.000						250.00	750.00

Example 13

Compound of formula I Capsule 1.0mg
						Material (chemical name)		Function(s)	Percentage of formulation (% w/w)	Unit dose (mg)	Typical batch size (g)

Compound of formula I Capsule 1.0mg
						Inside grain	A compound of formula I	Activating agent	0.40	1.00	3.000
Pregelatinized corn starch, EP/BP/NF	Diluent	73.30	183.25	549.75
					Microcrystalline cellulose, EP		Diluent/decomposer	10.00	25.00	75.00
Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
					Sodium dodecyl sulfate, EP/NF		Surface active agent	1.00	2.50	7.50
Extragranular	Microcrystalline cellulose, EP	Diluent/decomposer	10.00	25.00							75.00
					Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00

	Colloidal silica, EP/NF	Sliding agent	0.30	0.75	2.25
						Magnesium stearate, EP/BP	Lubricant agent	1.00	2.50	7.50
	Total of			100.000	250.00						750.00

Example 14

Compound of formula I Capsule 10mg
						Material (chemical name)		Function(s)	Percentage of formulation (% w/w)	Unit dose (mg)	Typical batch size (g)

Compound of formula I Capsule 10mg
						Inside grain	A compound of formula I	Active agent	4.00	10.00	30.00
Pregelatinized corn starch, EP/BP/NF	Diluent	69.70	174.25	522.75
					Microcrystalline cellulose, EP		Diluent/decomposer	10.00	25.00	75.00
Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
					Sodium dodecyl sulfate, EP/NF		Surface active agent	1.00	2.50	7.50
Extragranular	Microcrystalline cellulose, EP	Diluent/decomposer	10.00	25.00							75.00
					Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
	Colloidal silica, EP/NF	Sliding agent	0.30	0.75						2.25
					Magnesium stearate, EP/BP	Lubricant agent	1.00	2.50	7.50
	Total of			100.000						250.00	750.00

Example 15

Compound of formula I Capsule 100mg
						Material (chemical name)		Function(s)	Percentage of formulation (% w/w)	Unit dose (mg)	Typical batch size (g)

Compound of formula I Capsule 100mg
						Inside grain	A compound of formula I	Active agent	40.00	100.00	300.00
Pregelatinized corn starch, EP/BP/NF	Diluent	33.70	84.25	252.75
					Microcrystalline cellulose, EP		Diluent/decomposer	10.00	25.00	75.00

	Sodium starch glycolate, EP	Decomposing agent	2.00	5.00	15.00
						Sodium dodecyl sulfate, EP/NF	Surface active agent	1.00	2.50	7.50
	Extragranular	Microcrystalline cellulose, EP	Diluent/decomposer	10.00	25.00						75.00
Sodium starch glycolate, EP						Decomposing agent	2.00	5.00	15.00
		Colloidal silica, EP/NF	Sliding agent	0.30	0.75					2.25
Magnesium stearate, EP/BP						Lubricating deviceLubricating agent	1.00	2.50	7.50
		Total of			100.000					250.00	100.000

Examples 16 to 20

Batch size: 1kg of

Compound tablet of formula I (70mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)

Compound tablet of formula I (70mg)
				Inside grain	A compound of formula I	14.29	10.00
Medicinal lactose 200M	56.51	39.56
			Avicel PH101		5.00	3.50
Povidone K30	3.00	2.10
			Sodium starch glycolate		2.00	1.40
Tween 80V	0.20	0.14
			Water (W)		qs	qs
Extragranular	Avicel PH101	17.50					12.25
			Sodium starch glycolate	2.00	1.40
	Magnesium stearate	0.50				0.35
			Total of		100.00		70.00

The following parameters were used to make tablets of 70mg of the composition given in the table above.

Example numbering	Pressure setting	Average hardness (Kp)	Average thickness (mm)
				16	19	1.81	3.348
17	21	7.11	2.944
				18	23	8.10	2.875
19	25	8.56	2.864

20

27

8.85

2.886

Examples 21 to 25

Batch size: 1kg of

Compound tablet of formula I (70mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)
Inside grain	A compound of formula I	0.43	0.30
				Medicinal lactose 200M	68.37	47.86
	Avicel PH101	5.00	3.50
				Povidone K30	4.00	2.80
	Sodium starch glycolate	2.00	1.40
				Tween 80V	0.20	0.14
	Water (W)	qs	qs
				Extragranular	Avicel PH101	17.50	12.25
Sodium starch glycolate	2.00	1.40
			Magnesium stearate		0.50	0.35
Total of		100.00					70.00

The following parameters were used to make tablets of 70mg of the composition given in the above table (hardness and thickness parameters measured before possible coating):

example numbering	Pressure setting	Average hardness (Kp)	Average thickness (mm)
				21	19	1.52	3.339
22	21	5.77	3.048
				23	23	6.32	2.989
24	25	6.88	3.059

Example numbering	Pressure setting	Average hardness (Kp)	Average thickness (mm)
				25	27	6.95	3.006

Examples 26 to 30

Batch size: 1kg of

Compound tablet of formula I (70mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)
Inside grain	A compound of formula I	0.43	0.30
				Medicinal lactose 200M	68.37	47.86

	Avicel PH101	5.00	3.50
				Povidone K30	3.00	2.10
	Sodium starch glycolate	2.00	1.40
				Tween 80V	0.20	0.14
	Water (W)	qs	qs
				Extragranular	Avicel PH101	17.50	12.25
Sodium starch glycolate	2.00	1.40
			Magnesium stearate		1.50	1.05
Total of		100.00					70.00

The following parameters were used to make tablets of 70mg of the composition given in the above table (hardness and thickness parameters measured before possible coating):

example numbering	Pressure setting	Average hardness (Kp)	Average thickness (mm)
				26	19	2.23	2.774
27	20	2.53	2.734
				28	21	2.88	2.713
29	22	3.30	2.699
				30	23	3.51	2.657

Example 31

Batch size: 500g

Using parameters analogous to those of examples 16-30 above, a 250mg tablet containing 1mg of a compound of formula I was prepared with the composition indicated in the following table:

a compound tablet of formula I (250mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)
Inside grain	A compound of formula I	0.40	1.00
				Starch 1500	74.60	186.50
	Avicel PH101	10.00	25.00
				Sodium starch glycolate	2.00	5.00
	Water (W)	qs	qs
				Extragranular	Avicel PH101	10.00	25.00
Sodium starch glycolate	2.00	5.00
			Magnesium stearate		1.00	2.50
Total of		100.00					250.00

Example 32

Batch size: 500g

Using parameters analogous to those of examples 16-30 above, 70mg of tablets containing 1mg of the compound of formula I and having a mean hardness of 4kP were prepared with the compositions indicated in the following table:

compound tablet of formula I (70mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)
Inside grain	A compound of formula I	1.43	1.00
				Lactose 200M	70.86	49.60
	Corn starch	20.00	14.00
				Povidone K30	3.00	2.10
	Sodium starch glycolate	2.00	1.40
				Tween 80V	0.14	0.10
	Water (W)	qs	qs
				Extragranular	Sodium starch glycolate	2.00	1.40
Magnesium stearate	0.57	0.40
			Total of		100.00	70.00

Example 33

Batch size: 500g

Using parameters analogous to those of examples 16-30 above, a 70mg tablet containing 1mg of a compound of formula I was prepared with the composition indicated in the following table:

compound tablet of formula I (70mg)
				Material (chemical name)		Percentage of formulation (% w/w)	Unit dose (mg)

Compound tablet of formula I (70mg)
				Inside grain	A compound of formula I	1.40	0.98
200M lactose	62.50	43.75
			Avicel PH101		5.00	3.50
Povidone K30	3.00	2.10
			Sodium starch glycolate		2.00	1.40
Tween 80V	0.10	0.07

	Tartaric acid	6.00	4.20
				Water (W)	qs	qs
	Extragranular	Avicel PH101	17.50				12.25
Sodium starch glycolate				2.00	1.40
		Magnesium stearate	0.50			0.35
Total of				100.00	70.00

Example 34

Batch size: 500g

Material	Percentage of formulation (% w/w)	Unit dose (mg)
			A compound of formula I	1.40	0.98
Anhydrous lactose	71.60	50.12
			Avicel PH112	22.50	15.80
Sodium starch glycolate	4.00	2.80

Material	Percentage of formulation (% w/w)	Unit dose (mg)
			Magnesium stearate	0.50	0.40
Total of	100.0	70.00

Example 35

Batch size: 500g

Material	Percentage of formulation (% w/w)	Unit dose (mg)
			A compound of formula I	1.40	0.98
Mannitol (SD200)	71.60	50.12
			Avicel PH112	22.50	15.80
Sodium starch glycolate	4.00	2.80
			Magnesium stearate	0.50	0.40
Total of	100.0	70.00

Example 36

Using the above OpadryA70 mg tablet containing 10mg of a compound of formula I as in example 17 above was prepared using the following specific coating parameters (NB: the amounts described for the solids and coating solutions allowed batch coating of 7300g of uncoated tablets).

% w/w tablet coating target (target for tablet coating)	4％
		The Weight (g) of the coating solids is required (Weight of solids required to coat)	292
% w/w of coating solution (coating solution)	20％
		The Weight (g) of the coating solution is required (Weight of coating solution required)	1460

Example 37

Using the above OpadryA70 mg tablet containing 10mg of a compound of formula I as in example 17 above was prepared using the following specific coating parameters (NB: the amounts described for the solids and coating solutions allowed batch coating of 7300g of uncoated tablets).

% w/w tablet coating target (target for tablet coating)	6％
		The solid Weight (g) of the coating is required (Weight o)f solids required to coat)	438
% w/w of coating solution (coating solution)	20％
		The Weight (g) of the coating solution is required (Weight of coating solution required)	2190

Example 38

Use of EUDRAGIT as described aboveMethod for the monolithic application of E PO coating A70 mg tablet (5 mm diameter, 3.1mm high) containing 10mg of the compound of formula I was prepared as described in example 17 above. The batch size of the uncoated tablets was 500 g. EUDRAGIT was used in the following amountsE PO, sodium dodecyl sulfate, stearic acid and magnesium stearate.

EUDRAGITE PO(g)	26.3
		Sodium dodecyl sulfate (g)	2.6
Stearic acid (g)	3.9
		Magnesium stearate (g)	9.2
Water (W)	238.4

Example 39

Use of EUDRAGIT as described aboveMethod for the monolithic application of E PO coating A70 mg tablet (5 mm diameter by 2.9mm high) containing 10mg of the compound of the formula I was prepared as described in example 17 above. The batch size of the uncoated tablets was 600 g. EUDRAGIT was used in the following amountsE PO, sodium dodecyl sulfate, stearic acid and magnesium stearate.

EUDRAGITE PO(g)	92.0
		Sodium dodecyl sulfate (g)	9.2
Stearic acid (g)	13.8
		Magnesium stearate (g)	32.2

EUDRAGITE PO(g)	92.0
		Water (W)	834.3

Experimental study of the pharmaceutical composition of the present invention:

dissolution test:

device for measuring the position of a moving object

The following materials were used for dissolution testing:

apparatus type USP 2: SOTAX AT7 dissolution test bed or equivalent, 6 x 1000ml dissolution vessel and 6 stirrers.

HPLC system Agilent 1100(ChemstationPlus) with data extraction.

Analytical balance METTLER AX 205 DR

Working conditions of devices such as Milli-Q gradient A10 MILLIPORE, F1KN 13093H

The following conditions were used for dissolution testing:

dissolving device

Temperature: 37.0 +/-0.5 DEG C

Speed: 50. + -.2 rpm

Volume: 900ml

Dissolution medium: buffer pH 6.8 with 0.05% Tween 80

Sample volume: 12ml (without changing medium)

Sampling time point: distributed at 5, 10, 15, 30, 45, 60min

HPLC parameters:

omicron stationary phase EC 250/3 Nucleodur C18 gravity 3 μm (cat.No.7600820.30)

Volume: 250 mm. times.3.00 mm 3 μm (Macherey-Nagel)

Mobile phase: equal degree

Injection volume 10 μ l

Omicron column temperature: 25 deg.C

Omicron temperature: 25 deg.C

Flow rate: 0.5ml/min

O pressure: 149 Bar

Detection wavelength: 260nm

O chromatographic time: for 10min

Mobile phase: 850ml of acetonitrile, 150 ml of water and 5ml of trifluoroacetic acid are mixed thoroughly. Degassed before use.

Scheme(s)

The 10l dissolution medium was prepared as follows: dilution with water 79.85g NaH₂PO₄.2H₂O、69.55g Na₂HPO₄And 5g of Tween 80 to a total volume of 10 l.

A reference standard solution of the compound of formula I was prepared as 2 replicates. One of the reference standard solutions will be used as a working reference standard solution and the other standard solution will be used as a control reference standard solution. A reference standard solution of a compound of formula I was obtained as follows:

55mg of the compound of the formula I are weighed into a 250ml measuring flask and 4ml of acetonitrile are added. The mixture was sonicated for 5 minutes. After complete dissolution of the compound of formula I, the dissolution medium is added to complete 250 ml. 10.0ml of this solution was taken with a pipette into a 200ml measuring flask and the dissolution medium was added to complete 250 ml. The concentration of the compound of formula I in the reference standard solution is therefore 11. mu.g/ml.

The dissolution sample solution was prepared as follows:

900ml of dissolution medium are transferred to each vessel of the dissolution apparatus. The dissolution medium was allowed to equilibrate in the dissolution batch at 37 ℃. + -. 0.5 ℃ for at least 30 minutes. To each container was added dropwise a tablet of 10mg of the compound of formula I. 12ml of sample solution was aspirated from each container at 5, 10, 15, 30, 45 and 60 minutes. No media change is required. The sample solution was immediately filtered through a Gelman 1 μm glass fiber acrodisk syringe filter into an HPLC vial and cooled to room temperature.

HPLC analysis was performed using the following injection sequence:

-injecting the dissolution medium once;

-6 consecutive injections of a working reference standard solution;

-injecting the control reference standard solution twice;

-injecting each sample solution once.

After 6 sample injections were performed, the working reference standard solution was re-injected to ensure that the system float value was within the limit (2.0%).

The following criteria must be met:

injecting the working reference standard solution for 6 times continuously; the% RSD from the response factor (i.e., the concentration of the reference solution divided by the peak area of the reference solution) should be ≦ 2.0%. The total RSD of the response factor of the compound of formula I in the working reference standard solution injected throughout the run should be ≦ 2.0%.

The relative difference between the average response factor of the working reference standard solution after 6 injections and the average response factor of the control reference standard solution after 2 injections is less than or equal to 1.5 percent.

The result can be calculated using the following formula:

V_n＝V-V_r(n-1)

wherein the content of the first and second substances,

dissolved compound of formula I in marked amount

C_nConcentration of compound of formula I in mg/ml for the nth injection

V is the initial volume of the dissolution medium in ml 900ml

V_rVolume of dissolution medium removed per injection, in ml

＝12ml

V_nThe nth injectionActual volume of dissolution medium in ml

Labeled amount of compound of formula I per tablet 10mg

N-th sampling

A_splPeak area of compound of formula I obtained from sample solution

A_stdPeak area of compound of formula I obtained from working reference standard solution

C_stdConcentration of compound of formula I in mg/ml working reference standard solution

W_stdWeight of compound of formula I in mg as working reference standard solution

P_stdPotency of compound of formula I as reference substance in%

DF_stdDilution factor of standard solution, 5,000ml in ml

Results of the pharmaceutical composition according to the invention:

when the compositions of examples 16-20 were tested using the illustrated protocol, the compositions exhibited a dissolution profile as shown in fig. 1 (where percent dissolution (Y-axis) is expressed as a function of time (min) (X-axis)).

Brief description of the drawings

Figure 1 shows the dissolution profiles of the compositions of examples 16-20.

Claims (6)

1. A stable pharmaceutical composition comprising:

a) the compounds of formula I as depicted below,

or a pharmaceutically acceptable salt, solvate, hydrate or morphological form thereof;

b) a filler selected from lactose monohydrate and microcrystalline cellulose;

c) a disintegrant selected from sodium starch glycolate or a combination consisting of sodium starch glycolate and polyvinylpyrrolidone;

d) a surfactant consisting of polysorbate in a total amount of 0.1-3 wt% based on the total weight of the pharmaceutical composition; and

e) a lubricant consisting of magnesium stearate.

2. The pharmaceutical composition of claim 1, wherein the total amount of polysorbate is 0.1-1 wt% based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition according to claim 1 or 2, wherein the polysorbate is polysorbate 80.

4. A pharmaceutical composition according to any one of claims 1 to 3 in the form of a capsule.

5. A pharmaceutical composition according to any one of claims 1 to 3 in the form of a tablet.

6. Use of a pharmaceutical composition according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of pulmonary hypertension.