HK1071847B - Dosage forms having prolonged active ingredient release - Google Patents

Description

Dosage form with extended active ingredient release

Technical Field

The present invention relates to solid, orally administrable pharmaceutical dosage forms for once-or twice-daily administration with extended release of the active ingredient, which contain 4-phenylbutyrate as active ingredient, to methods for their production and to their use in the treatment of various diseases, which diseases are known to be beneficially affected by the active ingredient.

Background

The sodium salt of 4-phenylbutanoic acid (sodium 4-phenylbutyrate) and its use in the treatment of various diseases such as benign prostatic hyperplasia, cancer, cystic fibrosis, HIV, kidney and liver failure, thalassemia and urea cycle disorders are known. For example, WO85/04805(Brusilow) discloses a method for removing waste nitrogen in humans wherein 4-phenylbutyrate is administered. DE19810383(Manhart et al) discloses 4-phenylbutyrate as an apoptosis inducer for the treatment of neoplasms. WO9937150(Pandolfi et al) discloses the use of retinoic acid and/or histone deacetylase inhibitors for the transcription therapy of cancer. WO 93/07866, WO9510271 or EP 725635(Samid) disclose compositions and methods using phenylacetic acid derivatives for the treatment and prevention of a number of pathologies, including cancer, AIDS, anemia, and severe β -chain hemoglobinopathies, which occur in a number of U.S. patents. WO 9856370(USP6,207,195, Walsh et al) discloses therapeutic nanospheres comprising sodium 4-phenylbutyrate for the treatment of cystic fibrosis by CFTR gene therapy. WO 9840078 (rephalei) discloses the therapeutic enhancement of alkylene oxide diesters and butyric acid derivatives by fatty acid beta-oxidation inhibitors.

4-phenylbutyric acid rapidly decomposes to phenylacetic acid in the human body by beta-oxidation. The acid removes glutamine from the cell, which is important for the growth of cancer. The deficiency of glutamine in cancer cells leads to apoptosis. To retard the rapid removal of 4-phenylbutyrate from the body, about 10-40g per patient is administered per day. Infusion solutions are also used in order to achieve and maintain a constant level of active ingredient in the plasma. However, these are not suitable for emergency treatment. The use of large amounts of 4-phenylbutyrate is also a commercial problem. The active compounds are very expensive and have to be taken for months up to years.

It would therefore be desirable to have a 4-phenylbutyrate formulation that avoids the problems associated with the use of large amounts of this compound. The formulation should be effective at lower dosages of the active ingredient. When administered repeatedly, a constant therapeutically effective plasma level should be provided, showing minimal fluctuations between the maximum and minimum concentrations of the active ingredient in the blood. Possible methods of reducing the injection time of the active ingredient and minimizing fluctuations can be achieved by controlling the dissolution of the active ingredient over a longer period of time than is the case with conventional formulations. By means of therapeutic systemsMethods for solving this problem are provided (F. Theeuwes, J. pharm. Sci., Vol.64, 12, 1987-. The drawback of the OROS system is that it is technically difficult to produce them.

A formulation with a slow release rate, providing low plasma level fluctuations (remaining constant over a relatively long period of time), would be desirable. Slow release or delayed release formulations are known in the pharmaceutical art. However, they cannot be used simply for specific problems, and must be designed independently for each active ingredient and for each indication. This requires some inventive design.

The rate of release of the active ingredient from the tablet or powder is influenced by the solubility characteristics of the active ingredient, which in turn depends on solubility, particle size, specific surface area, and interaction with other excipients. Dissolution may be retarded by means of a diffusion barrier in the core of the tablet or in the film coating. In principle, the delayed dissolution by means of a diffusion barrier in the core is often used, on the basis of which the technology is simple. It is possible to use various excipients, such as swelling agents, lipophilic substances or plastics, as diffusion barriers. The matrix, that is to say the homogeneous composition of matter, can be such that the release of the active ingredient takes place by diffusion of the dissolved active ingredient, in particular through water-filled pores in the tablet core, and, if desired, in the specific case by diffusion through a delay substance which must be in a suitable structural form for this purpose. Alternatively, the matrix may be in a form that undergoes slow erosion and in this way affects the delayed release of the active ingredient.

In all those cases, the diffusion pathway and active diffusion surface used for release varies with time. For this reason, it is clear that with matrix systems it is generally not possible to predict any release with linear kinetics, i.e. order 0, both in vivo and in vitro. In contrast, release is generally a function of the Square root of time (Square root dispersion; Higuchi; J.Pharm.Sci.52, 12, 1963, 1145). The effectiveness of the Higuchi law on hydrocolloid matrices has also been demonstrated in a number of publications (Ford et al, int. J. pharm., 24, 1985, 327-.

Therapeutic dosage forms in which the drug is incorporated into a soluble or erodable matrix would be desirable due to considerations of ease of their manufacture, low degree of variation between different manufacturing processes, and due to relatively low cost.

The use of hydrophilic gums, such as hydroxypropyl methylcellulose, as a delay matrix material is known and has been tested with a number of active ingredients. To date, no formulation has been suitable with 4-phenylbutyrate for the desired purpose.

It is not possible to calculate or generally predict the behavior of a particular drug when combined with a retarding excipient. Although the basic factors influencing the release from matrix systems have been well studied, the interaction between the retarding material and other excipients on the one hand and the active ingredient and other excipients on the other hand may influence the retarding action in various ways.

The problem of release kinetics is a multifactorial one. The main factors, in addition to the dissolution behavior of the active ingredient, are the rate of water absorption and the rate of expansion of the interface to be penetrated, the diffusion coefficient of the substance through the expanded mass and its thickness as a function of time. It can be clearly speculated that by the existence of a balance between the erosion of the tablet and the dissolution properties of the active ingredient, a release of level 0 is caused, so that the diffusion path of the substance remains constant during the dissolution time.

However, it is important to realize that it is not possible to predict whether the release rate will be of the 0 th order or any other order. It is necessary to select from a large number of known pharmaceutical excipients those which are suitable for the desired purpose and which are processed in the appropriate quantitative ratios, which must likewise be selected, in order to form an effective matrix system.

Problems of the invention

The problem underlying the present invention is to overcome the existing disadvantages of using 4-phenylbutyrate in the retardation and cure of various diseases. Since this substance and its beneficial healing capacity have been known for a long time, there is a prejudice against developing solid, orally administrable pharmaceutical dosage forms which are technically easy and inexpensive to produce and which will produce their therapeutic effect when applied once or twice daily in lower than usual amounts.

Pharmaceutical dosage forms that meet the requirements of reduced dosage without a reduction in therapeutic activity, can be more easily and cheaply produced, and can be more easily applied in extended rescue treatment are often a lucrative finding. The patient's treatment and the unexpected success achieved with it can be taken as a measure of the inventive step.

The present invention provides such unexpected dosage forms.

Detailed Description

The present invention relates to a pharmaceutical unit dosage form comprising a therapeutically effective amount of 4-phenylbutyrate, which has an extended release of the active ingredient and is suitable for alleviating and curing various diseases in human patients when orally administered to said patients once or twice a day.

Pharmaceutical unit dosage forms are in particular tablets and powders for introduction into capsules, for example hard gelatine capsules.

The 4-phenylbutyrate may be of the alkali metal or alkaline earth metal type, such as lithium, sodium, potassium, magnesium or calcium. Sodium salts are preferred. The unit dosage form contains from about 50 to 1000mg, preferably about 100 to 500mg, most preferably about 250mg of the active compound.

An extended release of the active ingredient is to be understood in particular as the release rate of the active ingredient over a period of about 6 to 12 or up to 24 hours.

The extended release or delayed release dosage form is a homogeneous matrix comprising about 20-80%, preferably about 35% by weight of 4-phenylbutyrate, either as a powder or preferably in the form of a tablet.

The term "about" as used herein before and after in relation to weight or other measurements should denote a possible deviation of +/-5 to 10%.

The matrix is provided by about 5-50%, preferably about 20% by weight of hydroxypropyl methylcellulose having a molecular weight in the range of about 20000-250000, and, depending on the desired release retarding properties, 2-25% by weight of release controlling excipients and optionally other pharmaceutically acceptable excipients to bring the dosage form to 100% by weight.

A therapeutically effective amount is that amount required to maintain the desired therapeutic effect, particularly inhibition of glutamate metabolism, over a period of about 24 hours. The therapeutically effective amount of the dosage form known so far is 10000-40000mg per day. In the present invention, the effective daily amount is significantly reduced. One unit dosage form contains about 20-1000mg of 4-phenylbutyrate, preferably about 250 mg. The effective dose when administered twice daily amounts to only 40-2000mg, preferably 500mg, per day.

In herbal medicine matrix is defined as a well-mixed homogenous composition of matter which can be compressed, formed into tablets or which can be introduced into capsules, preferably hard gelatin capsules, in powder form.

Tablets or capsules contain, for example, 100-500mg, preferably 250mg of active ingredient, for example sodium 4-phenylbutyrate.

Pharmaceutically acceptable release controlling excipients are lipophilic or hydrophilic substances (release retarding agents, release controlling agents) that improve the process of delaying the swelling of the matrix.

The hydrophilic release retarding agent is a solid polyethylene glycol, such as polyethylene glycol 4000 or 6000, or a polyvinylpyrrolidone, such as of various viscositiesOr(trade name of BASF GmbH) and vinylpyrrolidone/vinyl acetate copolymers, e.g. Kollidone(trade name of BASF GmbH).

The lipophilic release retarder is a pharmaceutically acceptable vegetable fat derivative having a melting point above 60 deg.C in the form of a solid tablet, such as vegetable fatty acid having a chain length of at least 16 carbon atoms, e.g. stearic acid C16, palmitic acid C18 or mixtures thereof, and especiallyVegetable oils hardened by perhydrogenation, e.g. hydrogenated castor oils, e.g. Cutina(trade name of Henkel) or hydrogenated cottonseed oil, e.g.Or(trade name of Mendell). To prepare tablets, the lipophilic release retardant must be suitable for tableting. About 2-25% release retardant is used, based on the final weight of the tablet or capsule.

The Hydroxypropylmethylcellulose (HPMC) preferably used in the present invention and representing the retardation principle is of the type 2208 USPXXII with a molecular weight of 20,000-250,000, preferably 20,000-120,000, preferably a viscosity of 100-15,000 cps. Particularly suitable is Methocel which produces the fastest expansionsTypes, e.g. Methocel K100M(Prochem Chemical Co.)、Methocel Methocel And Methocel(trade name: DOW CHEMICAL CO.) or a practically equivalent MetoloseOf the type, e.g. MetoloseMetolose And Metolose(trade name, Shin-Etsu Chemical Co.Ltd.). About 5-50 wt%, preferably 10-40 wt% HPMC is used, based on the final weight of the tablet or capsule fill.

Other excipients are fillers, lubricants and flow regulators, which likewise have an effect on the release kinetics, but a small effect.

The filler is corn starch, lactose, microcrystalline cellulose, mannitol or calcium hydrogen phosphate, and mixtures thereof. Useful are, for example, mixtures of 75% lactose and 25% microcrystalline cellulose, e.g. Cellactose(trade name of Meggle GmbH). The filler must be carefully selected in the appropriate amount and properly matched to the particular formulation. In addition, the compression performance should be noted. They are used in an amount such that the weight of the tablet is 100%.

Lubricants are, for example, magnesium stearate, suitable qualities of stearic acid, calcium stearate and mixtures thereof, magnesium stearate being preferred and it being used preferably in amounts of 0.1 to 1%, based on the final weight of the formulation.

Suitable agents (flow regulators) which contribute to the flowability of the powder to be encapsulated or compressed are, for example, highly disperse silicon dioxide, preferably present in amounts of from 0.25 to 1%, based on the final weight of the preparation.

The tablets may be provided with a neutral film coating or a film coating which delays the release of the active ingredient, that is to say, which produces a lag time. Film coatings resistant to gastric digestion are preferred.

Film coatings without retarding action consist, for example, of film formers, pigments, antisticking agents and plasticizers. Such film formers may consist of fast dissolving ingredients. In this case, hydroxypropyl methylcellulose of the 2910 USPXXII type with low viscosity, for exampleE5 or E15 (Dow Chemicals Ltd.) or 606(Shin-Etsu)。

The film coating with a retarding action can consist of a water-insoluble but water-permeable polymer which acts as a diffusion barrier and not only initially generates a lag time, but also the initially altered water penetration leads to an influence on the swelling behavior of the core over a long period of time. Preferred water-insoluble polymers are water-insoluble derivatives of methacrylic acid, e.g. methyl/ethyl acrylate, e.g.RS or RL andNE (trade name,pharma GmbH) and mixtures thereof.

The film coating may also contain the excipients customary in film coating processes, such as photo-protective pigments, for example iron oxide, in an amount of from about 40 to 80%, or titanium dioxide, in an amount of from about 100 to 150%, antisticking agents, for example talc, in an amount of from about 50 to 200%, and also suitable are plasticizers of the polyethylene glycol series, for example PEG 400 or PEG6000, which are matched to the polymer, or triethyl citrate, for example triethyl citrate, in the case of methacrylic acid derivativesRS/RL and NE in amounts of about 30-60% (percentages in each case being based on dry coating material). When using saidAqueous dispersions of type (la), Tween80 is then necessary as an aggregation inhibitor, for example.

For the preparation of the powder components to fill hard gelatin capsules, it is possible to use the same powder components as those used for the preparation of tablets. The release kinetics within the tablet also depend on geometric factors such as the shape and size of the tablet. Preference is given to biconvex tablets having a diameter of about 5 to 11mm, in particular 70 to 9mm, and a thickness of 3 to 10mm, in particular 6.8 mm.

Preferred tablets contain, for example:

-about 250mg of sodium phenylbutyrate,

-about 146mg 100 or 4000cps of hydroxypropyl methylcellulose type 2208 USPXXII,

-about 261mg of lactose,

about 30-60mg, especially 31.25mg, of microcrystalline cellulose (PH102, SelectChemie orMeggle)，

-about 10mg hardened vegetable oil, or e.g. talc,

-about 1.5mg magnesium stearate, and

-optionally about 1mg of highly dispersed silica,

so that the core made therefrom weighs about 0.7 g.

Advantageously, for example, by using a solution containing about 7850g of isopropanol, about 3360gL12.5, about 66g dibutyl phthalate, about 18.0g812, and about 56g of a colloidal dispersion of polyethylene glycol PEG 400, providing 24000 cores with film coatings in number.

For tablets containing 100 and 500mg of active ingredient, corresponding aliquots of excipients should be used.

A preferred pharmaceutical dosage form contains 250mg of 4-phenylbutyrate sodium, and in particular a tablet as described in example 1.

In a further embodiment, the invention relates to a process for the preparation of a pharmaceutical dosage form, characterized in that the dosage form is prepared in a conventional manner, according to the above description.

If desired, the ingredients of the tablet core are ground to the desired particle size, mixed homogeneously with one another simultaneously or in a specific sequence, and optionally granulated by wetting with water, dispersing and drying the granulated material. If the mixture is pelletized, the filler, flow agent and lubricant may be added to the pellets after pelletization. The mixture of core ingredients is compressed to form tablets having a hardness of about 50-100N, preferably 90N, or introduced as such into hard gelatin capsules.

Film coating is carried out in a conventional manner by mixing the ingredients of the film coating with water, coating the compressed tablet cores therewith and drying at about 30-40 c, preferably about 35 c.

In a further embodiment, the invention relates to the use of a pharmaceutical dosage form according to the invention for the treatment of a disease which can be influenced by said dosage form, said treatment comprising orally administering the pharmaceutical dosage form of the invention once or twice daily to a patient in need of treatment and to be treated.

Depending on the age and weight of the patient, the nature and severity of the disease and the general condition of the patient, and on the 4-phenylbutyrate to be administered, the dosage form used contains from about 100 to about 1000mg, preferably 250mg, of active ingredient.

Diseases which can be beneficially influenced by the dosage forms of the invention include, inter alia, benign prostatic hyperplasia, cancer, leukemia, cystic fibrosis, AIDS, kidney and liver diseases, thalassemia and urea cycle disorders. For example, treatment of prostate cancer may be carried out by administering a pharmaceutical tablet formulation containing 250mg of sodium 4-phenylbutyrate twice daily, for example in the morning and evening. After about 1 month of treatment, the therapeutic effect was evident when the pain had disappeared. Treatment may be continued for months or years until a satisfactory effect is observed or the patient is completely free of disease. Sodium 4-phenylbutyrate produces no side effects even after long periods of treatment.

The following examples illustrate the invention without, however, limiting it.

Example 1: production of sustained-release tablets containing 250mg of sodium 4-phenylbutyrate

A mixture of 6000.0g of sodium 4-phenylbutyrate from Triple Crown America, Inc., 6,280.0g of lactosumonohydracum, 3,500.0g of Methocel K100M Premium (Prochem) and 750.0g of Avicel PH102 (Select Chemie) was wetted with 4000.0g of aqua puricata (water purified by reverse osmosis) and dried in cold air for 18 hours. The mixture was forced through a sieve IVmm and dried under air at 40 ℃ for a further 10 hours. A mixture of 240.0g of talc and 30.0g of magnesium stearate is mixed over 20 minutes and the mixture is compressed into tablets each weighing 0.7g, having a thickness of about 6.8mm and a hardness of 90N. Yield: 24000 tablet cores.

Mixing using a Diosna mixer, drying in a Lukon drying chamber, drying with &Bosshard screener and compression with Korsch compression press EK II.

Cores with film coatings are provided, for example, by using a colloidal dispersion containing 7850g of isopropanol, 3360g of Eudragit L12.5, 66g of dibutyl phthalate, 18.0g of Miglyol 812, and 56g of polyethylene glycol PEG 400. The suspension was sprayed onto 24000 cores at 3.5atm and 25 ℃. The tablets with the film coating were dried at 35 c for at least 4 hours in a circulating air drying chamber.

Example 2; results of human testing

The following is a description of the treatment and test results obtained from human patients.

Patient nr.1, MM, born at 1909, 2 months and 5 days.

The patient showed prostate cancer at 24 days 4/1995 with a Prostate Specific Antigen (PSA) of 36. mu.g/l with a positive prostate biopsy indicating adenocarcinoma of the prostate. Positive bone scans indicated multiple bone metastases to the lumbar and thoracic vertebrae, ribs and pelvis. He underwent bilateral orchiectomy in 1996 at month 2 due to progressive bone pain. Until month 11 of 1998 he was not painful until he again suffered bone pain mainly in his back. He was then treated orally twice daily with 250mg of the delayed tablet of sodium phenylbutyrate of example 1. After four weeks he had no pain. He maintained this medication until month 6 of 2001 without any other symptoms of prostate cancer. PSA and alkaline phosphatase were always within the normal range.

No side effects due to the treatment were observed.

The 6-month work in 2002 showed no symptoms of active prostate cancer signs. He now remained in complete remission for 12 months.

Patients were born at 7 months and 24 days in 1919, nr.2, KR.

The patient showed pathological fracture of 8 th thoracic vertebra due to metastatic destruction at 3 months in 1997. On both sides, multiple biopsies of the slightly enlarged prostate were positive for adenocarcinoma. Bone scans indicated multiple resorption on ribs and spine. On 10 days 4 month 1997, he underwent bilateral orchiectomy. From 5 months 1997 up to 9 months 2000, 250mg of the sodium 4-phenylbutyrate tablet of example 1 was administered orally to him twice a day. The last 8 months examination in 2001 showed no symptoms. Bone scans showed no pathological resorption. 4-phenylbutyrate is very well tolerated without side effects.

After 20 months, he died from a secondary disease in remission. His autopsy revealed no tumor tissue in the prostate or elsewhere.

Patient nr.3, m.w., born on 3/11 days 1911.

In 10 months 1997, prostate biopsies were taken due to elevated PSA (17.5. mu.g/l), indicating prostate cancer. Treatment with LH-RH agonists (Decapeptyl delayed tablet monthly treatment). In 1998, his alkaline phosphatase started to rise from 132 to 167UI (normal < 110U/I). From 11 months 1998 he was treated orally twice a day with 250mg of the sodium 4-phenylbutyrate tablet of example 1. His PSA drops to an unmeasurable level, and his alkaline phosphatase gradually drops to 114U/I on 14.12.1999. He never complained of bone pain. He died of a heart attack due to congestive heart failure, 4 months and 24 days in 2000. 4-phenylbutyrate is very well tolerated without side effects.

Claims (27)

1. A pharmaceutical unit dosage form comprising as active ingredient a therapeutically effective amount of 4-phenylbutyrate having an extended release of the active ingredient, which is obtained by formulating a homogeneous matrix comprising 5-50% by weight of hydroxypropylmethylcellulose having a molecular weight of 20,000-250,000, and additionally 2-25% by weight of a release controlling excipient.

2. The pharmaceutical unit dosage form according to claim 1, which is obtained by formulating a matrix containing an additional 25% by weight of release-controlling excipients.

3. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix is a powder or a tablet.

4. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix comprises 20-80% by weight of 4-phenylbutyrate.

5. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix comprises 35% by weight of 4-phenylbutyrate.

6. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the 4-phenylbutyrate is of the alkaline or alkaline earth type.

7. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the 4-phenylbutyrate salt is a lithium, sodium, potassium, magnesium or calcium salt.

8. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the 4-phenylbutyrate salt is the sodium salt.

9. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the unit dosage form contains 50-1000mg of the active ingredient.

10. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the unit dosage form contains 100-500mg of the active ingredient.

11. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the unit dosage form contains 250mg of the active ingredient.

12. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the release rate of the active ingredient extends over a period of 6 to 12 hours.

13. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the release rate of the active ingredient extends over a period of up to 24 hours.

14. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix comprises, in addition to 4-phenylbutyrate, release-controlling pharmaceutically acceptable excipients to achieve a 100% weight of the dosage form.

15. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix comprises hydroxypropylmethylcellulose having a viscosity of 100-15,000 cps.

16. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the homogeneous matrix comprises 10-40% by weight of hydroxypropylmethylcellulose.

17. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the tablets are provided with a neutral film coating or a film coating delaying the release of the active ingredient.

18. The pharmaceutical unit dosage form according to claim 1 or 2, wherein the tablet is prepared in the following manner:

A) a mixture of 6000.0g of sodium 4-phenylbutyrate, 6,280.0g of lactosum monohydracum, 3,500.0g of Methocel K100M Premium, and 750.0g of Avicel PH102, obtained from Triple CrownAmerica, Inc., was wetted with 4000.0g of water purified by reverse osmosis,

B) drying the mixture in cold air for 18 hours,

C) the mixture was forced through a sieve IVmm and dried under air at 40 c for an additional 10 hours,

D) a mixture of 240.0g talc and 30.0g magnesium stearate was mixed over 20 minutes,

E) the mixture was compressed into tablets each weighing 0.70g, having a thickness of 6.8mm and a hardness of 90N to give 24000 tablet cores,

the tablet cores were provided with a film coating by spraying the suspension onto the 24000 cores using a colloidal dispersion containing 7850g isopropanol, 3360g Eudragit L12.5, 66g dibutyl phthalate, 18.0g Miglyol 812, and 56g polyethylene glycol PEG 400 at 3.5atm and 25 deg.C, and

F) drying the film-coated tablets in a circulating air drying chamber at a temperature of 35 deg.C

For 4 hours.

19. The pharmaceutical unit dosage form according to claim 1 or 2, characterized in that the extended release is achieved by hydroxypropylmethylcellulose having a molecular weight of 20,000-120,000 and a viscosity of 10-1500 cps.

20. The pharmaceutical unit dosage form according to claim 1 or 2, comprising 250mg of sodium 4-phenylbutyrate as active ingredient.

21. Pharmaceutical unit dosage form according to claim 1 or 2, characterised in that it comprises

-about 250mg of sodium phenylbutyrate,

-about 146mg of a hydroxypropyl methylcellulose type 2208 USPXXII of 100 or 4000cps,

-about 261mg of lactose,

-about 30-60mg, especially 31.25mg microcrystalline cellulose,

-about 10mg hardened vegetable oil or talc,

-about 1.5mg magnesium stearate, and

-optionally about 1mg of highly dispersed silica,

so that the core made therefrom weighs about 0.7g,

wherein the term "about" indicates that the allowable deviation is ± 5-10%.

22. Pharmaceutical unit dosage form according to claim 1 or 2, characterised in that it comprises

-250mg of sodium phenylbutyrate,

146mg of hydroxypropyl methylcellulose type 2208 USP XXII of 100 or 4000cps,

-261mg of lactose,

-31.25mg of microcrystalline cellulose,

-10mg of hardened vegetable oil or talc,

-1.5mg of magnesium stearate, and

-optionally 1mg of highly dispersed silica.

23. Pharmaceutical unit dosage form according to claim 1 or 2, characterised in that 24000 cores are provided with a film coating produced from about 7850g isopropanol, about 3360g methyl/ethyl acrylate, about 66g dibutyl phthalate, about 18.0g of a mixture of 50-60% caprylic acid and 30-40% capric triglyceride and about 56g polyethylene glycol PEG 400, wherein the term "about" indicates that a deviation of ± 5-10% is allowable.

24. Pharmaceutical unit dosage form according to claim 1 or 2, characterised in that 24000 cores are provided with a film coating produced from 7850g of isopropanol, 3360g of methyl/ethyl acrylate, 66g of dibutyl phthalate, 18.0g of a mixture of 50-60% caprylic acid and 30-40% capric acid triglycerides and 56g of polyethylene glycol PEG 400.

25. A process for the preparation of a pharmaceutical unit dosage form according to any of claims 1 to 24, characterized in that the dosage form is prepared in a conventional manner.

26. Use of a pharmaceutical unit dosage form according to any of claims 1 to 24 for the manufacture of a medicament for the alleviation and treatment of various disorders in a patient by oral administration to said patient once or twice daily.

27. Use of a pharmaceutical unit dosage form as defined in claim 26 for the manufacture of a medicament for the treatment of benign prostatic hyperplasia, cancer, leukemia, cystic fibrosis, AIDS, renal or hepatic disease, thalassemia or urea cycle disorders by oral administration to a patient in a therapeutically effective amount thereof.

28. Use of a pharmaceutical unit dosage form as defined in claim 26 for the manufacture of a medicament for the treatment of prostate adenocarcinoma by oral administration to a patient of 250mg of sodium 4-phenylbutyrate thereof twice daily.