Patent 6,964,780

The invention provides controlled-release formulations for oral administration containing a cGMP PDE-5 inhibitor. The formulations are useful, inter alia, in the treatment or prevention of sexual dysfunction.

Description of the Invention

This invention relates to controlled-release oral pharmaceutical formulations of cGMP PDE-5 inhibitors, and to methods of treatment involving them.

Controlled-release oral pharmaceutical formulations are known. Their purpose is to modify the rate of drug release, for example to produce a constant rate of release of a drug into the gastrointestinal tract of a patient, or to delay the release of a drug into the gastrointestinal tract of a patient (see 'Sustained and Controlled Release Drug Delivery Systems', pp 3-6, edited by J R Robinson, published by Marcel Dekker Inc).

Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that catalyse the degradation of cyclic nucleotides. Cyclic nucleotides, particularly cAMP (i.e. cyclic adenosine 3′,5′-monophosphate), are important intracellular second messengers. PDEs are one cellular component that regulates the concentration of cyclic nucleotides. In recent years, at least seven PDE enzymes (such as PDE-1-PDE-7), as well as many subtypes of these enzymes, have been defined based on substrate affinity and cofactor requirements (J A Beavo and D H Reifsnyder, Trends Pharmacol Sci 11:150 [1990]; and J Beavo, in 'Cyclic Nucleotide Phosphodiesterases: Structure, Regulation and Drug Action', (Editors J Beavo and M D Housley). Wiley, Chichester, pp. 3-15 [1990]).

PDE-5 is a cGMP (i.e. cyclic guanosine 3′,5′-monophosphate) specific PDE. It has been shown that PDE-5 is an important enzyme in regulating the physiological response to sexual stimulation, and that inhibitors of the enzyme are useful in the treatment of sexual dysfunction.

In males, sexual dysfunction may be defined as the inability to obtain or sustain a penile erection adequate for satisfactory sexual intercourse. In females, sexual dysfunction may be defined as deficient physiological response to sexual stimulation and/or a deficient subjective feeling of arousal.

A cGMP PDE-5 inhibitor of particular interest is sildenafil {5-[2-ethoxy-5-(4-methyl-1-
piperazinylsulphonyl)phenyl]-1,6-dihydro-1-methyl-3-propylpyrazolo[4,3-d]pyrimidin-
7-one.

The compound was first disclosed in European Patent Application 463756, and its use in the treatment of sexual dysfunction was disclosed in International Patent Application WO 94/28902. A formulation of the citrate salt (VIAGRA™) was made available for the treatment of male erectile dysfunction in a number of countries including the USA in 1998. VIAGRA™ is an immediate release tablet that is administered about 1 hour before an effect is required, and the half-life of the drug in human plasma is about 4 hours after administration.

The main interest in the art so far has been to provide a fast-acting treatment of sexual dysfunction, which can provide an effect as soon as possible after administration. For example. International Patent Application WO 98/30209 discloses a rapidly releasing formulation of sildenafil citrate.

International Patent Application WO 97/18814 discloses controlled-release pharmaceutical formulations for oral administration consisting essentially of an active ingredient, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers. It is suggested therein that sildenafil could be delivered using the disclosed formulations. However, the advantages given below for controlled-release formulations of cGMP PDE-5 inhibitors were not mentioned.

International Patent Application WO 98/48781 (published on 5 Nov. 1998, after the priority date of the present application) discloses compositions providing "relatively slow release" of compounds including apomorphine (which is not a cGMP PDE-5 inhibitor). The formulations are indicated in the treatment of sexual dysfunction.

According to the present invention, there is provided a controlled-release formulation for oral administration containing a cGMP PDE-5 inhibitor; provided that the formulation does not consist essentially of sildenafil, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers.

Usually, formulations according to the invention will be tablets or capsules that are swallowed. However, the invention also includes buccal formulations (which may be tablets, ointments, gels or patches).

Controlled-release formulations may be divided into sustained-release and pulsatile-release formulations (also known as delayed-release formulations). In general, such formulations are known to those skilled in the art or are available using conventional methods.

Sustained-release dosage forms release their active ingredient into the gastro-intestinal tract of a patient over a sustained period of time following administration of the dosage form to the patient. Particular dosage forms include:

(a) those in which the active ingredient is embedded in a matrix from which it is released by diffusion or erosion (see Example 1 below);

(b) those in which the active ingredient is present in a core which is coated with a release rate-controlling membrane (see Example 3 below);

(c) those in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient;

(d) those in which the active ingredient is released through a semi-permeable membrane, allowing the drug to diffuse across the membrane or through liquid filled pores within the membrane; and

(e) those in which the active ingredient is present as an ion exchange complex.

The dosage forms mentioned in (a), (b) and (c) above are of particular interest.

When several cores are present, for example coated cores in the dosage forms mentioned in (b) and (c), such formulations are sometimes referred to as "multiparticulates".

It will be apparent to those skilled in the art that some of the above means of achieving sustained-release may be combined, for example a matrix containing the active compound may be formed into a multiparticulate and/or coated with an impermeable coating provided with an aperture.

Pulsatile-release formulations release the active compound after a sustained period of time following administration of the dosage form to the patient. The release may then be in the form of immediate- or sustained-release. This delay may be achieved by releasing the drug at particular points in the gastro-intestinal tract or by releasing drug after a pre-determined time. Pulsed-release formulations may be in the form of tablets or multiparticulates or a combination of both. Particular dosage forms include:

1. osmotic potential triggered release (see U.S. Pat. No. 3,952,741);

2. compression coated two layer tablets (see U.S. Pat. No. 5,464,633);

3. capsules containing an erodible plug (see U.S. Pat. No. 5,474,784);

4. sigmoidal releasing pellets (referred to in U.S. Pat. No. 5,112,621); and

5. formulations coated with or containing pH-dependent polymers including shellac, phthalate derivatives, polyacrylic acid derivatives and crotonic acid copolymers.

Dual release formulations can combine the active ingredient in immediate release form with additional active ingredient in controlled-release form. For example, a bilayer tablet can be formed with one layer containing immediate release active ingredient and the other layer containing the active ingredient embedded in a matrix from which it is released by diffusion or erosion. Alternatively, one or more immediate release beads can be combined with one or more beads which are coated with a release rate-controlling membrane in a capsule to give a dual release formulation. Sustained release formulations in which the active ingredient is present in a core provided with an outer coating impermeable to the active ingredient, the outer coating having an aperture (which may be drilled) for release of the active ingredient, can be coated with drug in immediate release form to give a dual release formulation. Dual release formulations can also combine drug in immediate release form with additional drug in pulsed release form. For example, a capsule containing an erodible plug could liberate drug initially and after a predetermined period of time further drug in immediate- or sustained-release form.

Thus, according to the invention, there is further provided a dual release formulation for oral administration having a first portion comprising a controlled-release formulation as defined above, but without proviso, and a second portion comprising a cGMP PDE-5 inhibitor in immediate release form. The invention also provides products containing a controlled-release formulation as defined above, but without proviso, and a cGMP PDE-5 inhibitor in immediate release form, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of sexual dysfunction.

Preferably, formulations according to the present invention are sustained-release formulations. For example, it is preferred that up to 75% by weight of the active ingredient is released from the formulation into the gastrointestinal tract (or in a model of the GI tract) after a period of time in the range 1-24 hours following administration, for example 6-18 hours. A suitable model of the GI tract is described in Example 2 below.

Dual release formulations as defined above are also of particular interest. It is preferred that the first portion of such formulations is a sustained-release formulation.

An advantage of controlled-release, particularly sustained-release formulations according to the present invention is that a patient receiving them would have improved sexual function for a sustained period of time following administration (such as 6-24 hours, for example 12-18 hours), and so be ready for sexual activity at almost any time. This would allow a more spontaneous sex-life to be pursued.

In addition, it is thought that in male patients at risk of developing sexual dysfunction (for example diabetic patients or patients having undergone nerve sparing radical prostatectomy), the prevalence of nocturnal erections is diminished. Nocturnal erections may play an important role in preserving normal erectile function by providing regular tissue oxygenation thus preventing tissue fibrosis and erectile degeneration. Thus, a cGMP PDE-5 inhibitor delivered to a patient during sleep will increase the ability of at-risk individuals to have nocturnal erections, increase tissue oxygenation, prevent penile fibrosis and thus preserve erectile function or slows its decline. Controlled-release formulations may be of particular use in this instance, providing cGMP PDE-5 inhibition throughout the sleeping period.

A further advantage of formulations according to the present invention is that side effects may be reduced. For example, although sildenafil offers a safe, effective and generally very well tolerated oral treatment for male erectile dysfunction, dose-related reversible side effects such as headache or visual disturbance at high dosage may limit its use in a minority of patients. Such effects are mediated by systemic exposure to sildenafil following oral administration: thus a formulation with a sustained release profile, which avoids initial high plasma concentrations, could be of great value to these patients.

Preferably, the cGMP PDE-5 inhibitor is sildenafil, or a pharmaceutically acceptable salt thereof (such as the citrate salt).

Other cGMP PDE-5 inhibitors (previously mentioned in WO 94/28902) that may be mentioned include:

5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one.

5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-allyloxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-
dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-
1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{2-ethoxy-5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]phenyl}-1-methyl-3-n-
propy- 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-{5-[4-(2-hydroxyethyl)-1-piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-
n -propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one;

5-[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-
dihydro -7H-pyrazolo[4,3-d]pyrimidin-7-one; and

5-[2-ethoxy-5-(1-methyl-2-imidazolyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H
-pyrazolo[4,3-d]pyrimidin-7-one.

The following cGMP PDE-5 inhibitors (previously mentioned in WO 97/03675 to Laboratoire Glaxo Wellcome SA) may also be mentioned:

(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) -
pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione; and

(3S,6R,12aR)-2,3,6,7,12,12a-hexahydro-2,3-dimethyl-6-(3,4-
methylenedioxyphenyl) -pyrazino[2′,1′:6,1]pyrido[3,4-b]indole- 1,4-dione.

When the formulation includes a matrix in which the active ingredient is embedded (such as a matrix tablet), it preferably contains hydroxypropylmethyl cellulose. Preferably, the hydroxypropylmethyl cellulose has a number average molecular weight in the range 80,000-250,000. Preferably, the hydroxypropylmethyl cellulose has a degree of methyl substitution in the range 19-30%. Preferably, the hydroxypropylmethyl cellulose has a degree of hydroxy substitution in the range 7-12%. A number of hydroxypropylmethyl cellulose polymers are available commercially under the brand name Methocel™, and some of those suitable for use in formulations according to the invention are given in the table below:

				Nominal
	Number	Degree of	Degree of	viscosity of a
Methocel ™	average	methyl	hydroxy	2% aqueous	USP
grade	MW	substitution	substitution	solution	designation

K4M	89000	19-24%	7-12%	4000 cps	2208
K15M	125000	"	"	15000 cps	"
K100M	215000	"	"	1000000 cps	"
E4M	93000	28-30%	7-12%	4000 cps	2910
E10M	113000	"	"	10000 cps	"
F4M	90000	27-30%	4-7.5%	4000 cps	2906
@ Methocel ™ K4M has characteristics of particular interest.

It will be apparent to those skilled in the art that the hydroxypropylmethyl cellulose may consist of molecules of different chain lengths, but that the average chain length gives a molecular weight in the range stated.

Matrix formulations according to the present invention may contain a buffering agent. This is particularly useful when the formulation contains sildenafil citrate. A buffering agent of particular interest is aspartic acid. When it forms part of a matrix tablet, aspartic acid acts as a buffering agent to maintain a low pH at the surface of the tablet. Because sildenafil citrate has a low solubility at pH values greater than 6, the acid keeps the drug relatively soluble during the transit of the tablet through the GI tract. When present, aspartic acid will typically make up 15-30% by weight of the formulation.

The formulations of the present invention may include tabletting excipients, for example colloidal anhydrous silica, polyvinylpyrrolidone, lactose and magnesium stearate. Lactose is of particular interest, and when present it will typically make up 10-40% by weight of the formulation.

Formulations according to the invention may be provided additionally with a cosmetic coating: for example a coating comprising a pigment, a plasticizer and a polymer such as OPADRY™ (manufactured by Colorcon), or a sugar coating. Such coatings do not substantially affect the performance of the formulation, but enhance its presentation. Such coatings may be applied by spraying tablet cores with a solution of the components, using conventional techniques.

Preferably, in matrix formulations according to the present invention, the hydroxypropylmethyl cellulose makes up 10-50% by weight of the formulation.

When the formulation has a core comprising the active ingredient which is coated with a release rate-controlling membrane, it is preferred that several such coated cores are present (i.e. the formulation is multiparticulate). For example, 100 or more coated cores may be filled into a capsule. Preferably, the core also includes a buffering agent (such as succinic acid). The release rate-controlling membrane may comprise an ammonio methacrylate copolymer and a plasticizer.

Preferably, in formulations according to the present invention, the cGMP PDE-5 inhibitor makes up 5-50% by weight of the formulation.

Preferably, in formulations according to the present invention, the rate at which the cGMP PDE-5 inhibitor is released therefrom is substantially independent of the pH of the surroundings.

The present invention also provides processes for the production of the sustained release pharmaceutical formulations set out in (a), (b) and (c) above, which include the steps of:

(a) mixing the cGMP PDE-5 inhibitor with a matrix material, and pressing into tablets;

(b) forming a core comprising the cGMP PDE-5 inhibitor and then coating the core with a release rate-controlling membrane; or

(c) forming a core containing the cGMP PDE-5 inhibitor and then coating the core with a coating impermeable to the cGMP PDE-5 inhibitor:
respectively.

The invention further provides the use of a cGMP PDE-5 inhibitor in the manufacture of a formulation for the treatment or prevention of sexual dysfunction; characterized in that, following administration, the formulation releases the inhibitor over or after a sustained period of time. Consequently, following administration, the mammal's sexual function will be substantially improved for or after a sustained period of time.

Usually, the mammal will be a human, but administration to other mammals, such as horses, is contemplated.

A "sustained period of time" in relation to the improvement in sexual function is a period of time such as 6≧24 hours, for example 12≧18 hours.

It will be appreciated by those skilled in the art that the formulations of the present application may also be administered to patients suffering from or at risk of suffering from disorders other than sexual dysfunction, but in which cGMP PDE-5 inhibitors may be useful therapeutically.

The invention further provides a method of treating or preventing sexual dysfunction, which comprises administering a controlled-release formulation of a cGMP PDE-5 inhibitor, as defined above, but without proviso, to a mammal in need of such treatment or prevention. Consequently, the mammal's sexual function is substantially improved for or after a sustained period of time.

The invention further provides a method of improving sexual function in a mammal (not suffering from sexual dysfunction), which comprises administering a controlled-release formulation of a cGMP PDE-5 inhibitor, as defined above, but without proviso, to the mammal. Consequently, the mammal's sexual function is substantially improved for or after a sustained period of time.

The invention further provides a method of increasing the probability of a nocturnal erection in a male mammal, which comprises administering a controlled-release formulation, as defined above, but without proviso, to the male mammal.

Formulations according to the invention will usually be administered once a day, or possibly twice a day. The total daily dosage of a cGMP PDE-5 inhibitor (such as sildenafil citrate) is usually in the range 25-400 mg, preferably 50-200 mg. Thus, a once daily formulation according to the invention will usually contain 25-400 mg of drug substance (such as sildenafil citrate), preferably 50-200 mg.

Claim 1 of 26 Claims

1. A sustained-release formulation for oral administration containing a cGMP PDE-5 inhibitor, which comprises a core containing the cGMP PDE-5 inhibitor and an outer coating impermeable to the cGMP PDE-5 inhibitor, the outer coating having an aperture for release of the cGMP PDE-5 inhibitor, provided that the formulation does not consist essentially of sildenafil, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers.

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