WO1997047311A1 - Coated compositions containing polyene derivatives - Google Patents
Coated compositions containing polyene derivatives Download PDFInfo
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- WO1997047311A1 WO1997047311A1 PCT/EP1997/002056 EP9702056W WO9747311A1 WO 1997047311 A1 WO1997047311 A1 WO 1997047311A1 EP 9702056 W EP9702056 W EP 9702056W WO 9747311 A1 WO9747311 A1 WO 9747311A1
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- pharmaceutical composition
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- film coating
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- mepartricin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Definitions
- the present invention describes new pharmaceutical compositions comprising polyene derivatives, useful for the treatment of pathologies due to the umbalance of estrogen hormones in humans.
- Polyene compounds obtained from the fermentation broths of particular strains of Streptomyces, are polyunsaturated macrolides containing up to seven conjugated double bonds.
- Polyenes also frequently show a high toxicity to human beings, due to their strong affinity toward cholesterol of mammalian cell membranes, f.i. of red blood cell membranes.
- partricin basically constituted by two components A and B (The Merck Index, 12th Ed. n. 7181) .
- partricin A and partricin B derivatives in particular the C1-C3 alkyl or aminoalkyl esters and the C1-C3 alkyl or aminoalkyl amides thereof, eventually N'-acylated or aminoacylated, have marked antifungal action, together with, generally, a toxicity definitely lower than that of partricin.
- BPH benign prostatic hypertrophy
- Benign prostatic hypertrophy is due to uncontrolled growth of various cell components of the prostatic gland. According to some Authors the incidence of this affection involves approximately 50% of the male population aged 50 to 60 years and tends to increase with increasing age. In view of the progressive lengthening of mean life expectation, benign prostatic hypertrophy is doubtless to be regarded as a disease of great social implication, quite limiting the operative capacity of the subjects affected, owing to the troublesome symptomatology leading to frequent infective complications in the urinary tract, and requiring treatments the cost of which falls mainly on national health budgets.
- partricin methyl ester USAN: mepartricin
- Mepartricin absence of toxicity is due to its exclusively topical mechanism of action at intestinal level, no substantial quantities of drug being found in the systemic circulation, while its effects on BPH were thought to occur through complexation of cholesterol, a substance regarded as one of the major etiologic factors of this pathology, since able to accumulate and precipitate in the prostatic gland and because a precursor of various steroid hormones.
- Mepartricin at the doses indicated in the above mentioned USA Patent no.
- partricin derivatives are not excellent from a chemical point of view since they are rapidly degraded by both the gastric juices and the atmospheric oxygen.
- Administration of partricin derivatives cannot therefore forgo from a pharmaceutical composition ensuring that the active ingredient reaches the site of action (the intestine) without interacting with the atmospheric oxygen and humidity and with the gastric juices which would inactivate it.
- the formulations described in the already mentioned patent underwent in time, specially in hot countries, a marked decrease in the content of active ingredient .
- a pharmaceutical composition has now surprisingly been discovered, and makes one of the subjects of the present invention, comprising a polyene derivative as the active ingredient, an inner gastroresistant film coating comprising a copolymer of methacrylic acid and ethyl acrylate, and an outer protective film coating comprising a water-soluble polymer and a polysaccharide, where the ratio between the gastroresistant film coating and the protective film coating ranges from 4:1 to 1:4, preferably 2:1 to 1:2, and where the quantity of the said films makes up the 2 to 20% of the final weight of the pharmaceutical composition.
- the pharmaceutical composition of the present invention is preferably administered in the form of tablets, capsules, and granules.
- the particular combination of the gastro-resistant film coating with the protective film coating of the present invention permits to surprisingly obtain optimum preservation results even in hot climates, as regards both the titre of the active ingredient and as regards gastroresistance and disintegration of the pharmaceutical composition, preferably in the form of tablets, even after prolonged ageing.
- the gastroresistant film coating is essentially made up of a copolymer of methacrylic acid and ethyl acrylate, while the protective film coating is made up of the combination of a polysaccharide (i.e., dextrin, dextran, pullulan) in the function of a sealing agent and of a water-soluble polymer as a filmogenic agent.
- a polysaccharide i.e., dextrin, dextran, pullulan
- the purpose of the latter is substantially to favour a uniform and unbroken application of the protective film coating and consists of a water-soluble polymeric substance with high molecular weight, that may also belong to different groups of chemical products, provided it ensures the required filmogenic characteristics.
- a filmogenic agent of the cellulose group f.i., methylcellulose, hydroxy-propylmethylcellulose, hydroxy- propylcellulose, hydroxyethylcellulose
- the polyvinyl polymers group f.i., polyvinyl alcohol, polyvinylpyrrolidone
- one or more adjuvants could also be added, such as surface-active agents
- the pharmaceutical composition of the present invention comprises a derivative of partricin A and/or partricin B selected from the C1-C3 alkyl or aminoalkyl esters and amides thereof, optionally N'- acylated or amino-acylated.
- partricin derivatives can be used as such in the composition of the invention, or in a water- soluble form, obtained through salification with an acid (f.i. aspartic acid, ascorbic acid, glutammic acid) , or through complexation with a surface-active agent f.i., sodium laurylsulphate, sodium desoxycholate) .
- an acid f.i. aspartic acid, ascorbic acid, glutammic acid
- a surface-active agent f.i., sodium laurylsulphate, sodium desoxycholate
- Mepartricin, mepartricin A, N' -dimethylamino-acetyl partricin A 2-pyridilethylamide and the mepartricin/sodium laurylsulphate complex are the partricin derivatives most preferably used in the composition of the invention.
- the particular filmogenic combination of the present invention permits the preparation of pharmaceutical compositions, for example in the form of tablets resistant to the gastric juices, affording an unexpected long-term stability to the partricin derivatives and rapidly disintegrating in enteric environment, even after ageing at high temperatures.
- partricin derivatives comprised in the composition of the invention administered at doses (40-120 mg/die) sensibly higher than those presently used (26-39 mg/die) , lead to definitely better therapeutic results as regards both the symptomatology and the prostate size, even in patients with advanced BPH, who are commonly less sensitive to the present therapeutic doses of mepartricin.
- mepartricin was found able to bind not only with cholesterol but also with various androgen steroid hormones and, in particular, with estrogens, whose function in the cell stimulation process is known.
- pathologies we have particularly considered benign prostatic hypertrophy whose etiology is likely to be found in the altered ratio of estrogens to androgens .
- mepartricin helps elimination of the estrogens at intestinal level (increase of faecal excretion) since insoluble complexes are formed, decreases the circulating estrogen blood levels and reduces their biliary secretion (hence their enterohepatic recirculation) in correspondence with the main meals, with a circadian rhythm exhibiting its peak in the evening hours. For this reason a single daily administration of the total dose of mepartricin is preferable, to be given after the evening meal, or, at most, 2 daily administrations after the main meals and not 8-hourly as considered preferable in the documents coming before the present invention, supported also by mepartricin absence of oral toxicity.
- Preparation method Mix together the constituents of the core and compress the mixture using a compressing machine.
- Example 3 Formula for gastroresistant tablets containing 80 mg of active ingredient : Core
- Example 4 Formula for gastroresistant tablets containing 80 mg of active ingredient :
- Tablets prepared with 4 different formulations of mepartricin were stored in aluminium/aluminium blisters at 37°C and re-controlled for gastroresistance, disintegration time and titre of the active ingredient after 6 months.
- the formulations had the following characteri-stics : Formula I : 40-mg cores, like those in example 1, but coated with a gastroresistant film coating made up of cellulose acetophthalate dissolved in isopropyl alcohol and ethyl acetate and with a protective film coating made up of hydroxypropylmethylcellulose dissolved in isopropyl alcohol and chloroform.
- Formula II 40-mg cores, like those in example 1, but coated with a gastroresistant film coating made up of cellulose acetophthalate, rendered water-soluble through salification with ammonia and dissolved in water, and with a protective film coating made up of hydroxypropyl ⁇ methylcellulose dissolved in water.
- Formula III 40-mg cores, likethose described in example 1, but coated with a gastroresistant film coating only, made up like that in example 1.
- Formula IV 40-mg cores, like those in example 1, coated with both the gastroresistant film coating of example 1, and by the protective film coating again of example 1. The following table reports the results obtained:
- Formula II presents fair stability of the active ingredient but unsatisfactory disintegration of the tablets following accelerated ageing.
- Formula III solves the problem of disintegration of the tablets to the detriment however of mepartricin stability.
- Formula IV alone concomitantly and brilliantly solves the problems of gastroresistance, disintegration and chemical stability of the active ingredient.
- Group I mepartricin three 50,000 U (13 mg) tablets daily (8-hourly) for a total of 39 mg of mepartricin daily (US patent no. 4,237,117).
- Group II mepartricin two 40-mg tablets (formula of example 1) daily, following the main meals for a total of 80 mg daily.
- Group III mepartricin one 80-mg tablet daily (formula of example 2) following the evening meal. Before and after trial the following symptoms were recorded: pollakiuria, nocturia, force and caliber of stream, prostate size at transrectal echotomography. The following table reports the results obtained:
- 14 C-estradiol (0,5 ⁇ Ci) was incubated with bile and plasma obtained from untreated rats, for 1 hour at 37°C, in absence and presence of mepatricin in a total volume of 1 ml . At the end of the incubation period the samples were centrifuged and the radioactivity in supernatant was determined. Two mepartricin concentrations were tested: 1 and 3 mg/ml. The following table reports the results of the in vitro binding study of 14 C-estradiol to mepartricin in vehicle
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Abstract
The present invention concerns new pharmaceutical compositions, comprising polyene derivatives useful in the treatment of pathologies due to the unbalance of estrogen hormones in humans.
Description
COATEDCOMPOSITIONS CONTAINING POLYENEDERIVATIVES
DESCRIPTION The present invention describes new pharmaceutical compositions comprising polyene derivatives, useful for the treatment of pathologies due to the umbalance of estrogen hormones in humans.
Polyene compounds, obtained from the fermentation broths of particular strains of Streptomyces, are polyunsaturated macrolides containing up to seven conjugated double bonds.
They are usually sensitive to oxygen, water, temperature, etc., leading to chemical modifications and degradation, and the pharmaceutical formulations containing them have often a short shelf-life. They are usually endowed with high antibiotic activity and are effective, similarly to some of their synthetic derivatives, against some fungal strains, tipically belonging to the Candida, Aspergillus and Cryptococcus species, through an interaction with the ergosterol of the microbial membrane, which may lead at the end to cellular death.
Polyenes also frequently show a high toxicity to human beings, due to their strong affinity toward cholesterol of mammalian cell membranes, f.i. of red blood cell membranes.
Among these polyenes, one of the most effective compounds is represented by partricin, basically constituted by two components A and B (The Merck Index, 12th Ed. n. 7181) .
It is known that partricin A and partricin B derivatives, in particular the C1-C3 alkyl or aminoalkyl esters and the C1-C3 alkyl or aminoalkyl amides thereof, eventually N'-acylated or aminoacylated, have marked
antifungal action, together with, generally, a toxicity definitely lower than that of partricin.
In relatively more recent times these compounds were also found to be active against benign prostatic hypertrophy (BPH) (T. Bruzzese et al . , USA Patent no. 4,237,117; 1980) .
Benign prostatic hypertrophy is due to uncontrolled growth of various cell components of the prostatic gland. According to some Authors the incidence of this affection involves approximately 50% of the male population aged 50 to 60 years and tends to increase with increasing age. In view of the progressive lengthening of mean life expectation, benign prostatic hypertrophy is doubtless to be regarded as a disease of great social implication, quite limiting the operative capacity of the subjects affected, owing to the troublesome symptomatology leading to frequent infective complications in the urinary tract, and requiring treatments the cost of which falls mainly on national health budgets.
The medical approach to benign prostatic hypertrophy brought about considerable results thanks to the introduction in therapy of partricin methyl ester (USAN: mepartricin) , a compound with marked pharmacologic action coupled with good tolerance, unlike other products presenting a high incidence of undesired and harmful side effects. Mepartricin absence of toxicity is due to its exclusively topical mechanism of action at intestinal level, no substantial quantities of drug being found in the systemic circulation, while its effects on BPH were thought to occur through complexation of cholesterol, a substance regarded as one of the major etiologic factors of this pathology, since able to accumulate and precipitate in the prostatic
gland and because a precursor of various steroid hormones. Mepartricin, at the doses indicated in the above mentioned USA Patent no. 4,237, 117, that is, of 2-3 tablets daily, equivalent to 100,000 - 150,000 U/die (26-39 mg/die) , leads to considerable results, as regards both the symptomatology (day and night urinary frequency, force and caliber of stream) and the size of the prostate, in the majority of the patients treated. In a certain number of cases, considered to be not less than 30%, treatment with mepartricin was however unable to bring about results such as to allow further deferment of surgery, which entails considerable costs for the national health systems, not trifling risks for the patients, and a certain percentage of cases of impotence.
The posologic scheme too, envisaged in the aforesaid patent (one 50,000 U tablet every 8 or 12 hours) was found not quite optimum, since not only does it fail to favour patient's compliance, specially during long-term treatments, but, above all, subsequent acquisitions are disregarded, as explained further on.
It was also observed that the stability of partricin derivatives is not excellent from a chemical point of view since they are rapidly degraded by both the gastric juices and the atmospheric oxygen. Administration of partricin derivatives cannot therefore forgo from a pharmaceutical composition ensuring that the active ingredient reaches the site of action (the intestine) without interacting with the atmospheric oxygen and humidity and with the gastric juices which would inactivate it. The formulations described in the already mentioned patent, underwent in time, specially in hot countries, a marked decrease in the content of active ingredient .
In the formulations in tablet form, previously disclosed, a gastroresistant film coating was described, the application of which, with organic solvents, dangerous and polluting per se, entails a further risk of increasing the instability of the active ingredient owing to the fact that the solvents penetrate into the tablet core.
Subsequent experiments, aimed at excluding organic solvents from the formula of the gastroresistant film coating, led to improved chemical stability to the detriment of the tablet disintegration time, rapidly increasing with ageing of the tablets, beyond the limits fixed in the pharmacopoeias. Mention is to be made of the fact that even a decrease in the quantity of the film coating applied does not lead to the desired results, since the gastroresistant protection would by consequence be obliterated. Other solutions (i.e., changing the gastroresistant polymer) proved useless too. A pharmaceutical composition has now surprisingly been discovered, and makes one of the subjects of the present invention, comprising a polyene derivative as the active ingredient, an inner gastroresistant film coating comprising a copolymer of methacrylic acid and ethyl acrylate, and an outer protective film coating comprising a water-soluble polymer and a polysaccharide, where the ratio between the gastroresistant film coating and the protective film coating ranges from 4:1 to 1:4, preferably 2:1 to 1:2, and where the quantity of the said films makes up the 2 to 20% of the final weight of the pharmaceutical composition.
The pharmaceutical composition of the present invention is preferably administered in the form of tablets, capsules, and granules.
The particular combination of the gastro-resistant film coating with the protective film coating of the present invention, permits to surprisingly obtain optimum preservation results even in hot climates, as regards both the titre of the active ingredient and as regards gastroresistance and disintegration of the pharmaceutical composition, preferably in the form of tablets, even after prolonged ageing. The gastroresistant film coating is essentially made up of a copolymer of methacrylic acid and ethyl acrylate, while the protective film coating is made up of the combination of a polysaccharide (i.e., dextrin, dextran, pullulan) in the function of a sealing agent and of a water-soluble polymer as a filmogenic agent. The purpose of the latter is substantially to favour a uniform and unbroken application of the protective film coating and consists of a water-soluble polymeric substance with high molecular weight, that may also belong to different groups of chemical products, provided it ensures the required filmogenic characteristics.
Within the scope of the present invention, it was found that a filmogenic agent of the cellulose group (f.i., methylcellulose, hydroxy-propylmethylcellulose, hydroxy- propylcellulose, hydroxyethylcellulose) and of the polyvinyl polymers group (f.i., polyvinyl alcohol, polyvinylpyrrolidone) , lead to excellent results and may be advantageously added to the composition of the invention. To favour application of the gastroresistant film coating and of the protective film coating, to the above mentioned filmogenic agents one or more adjuvants could also be added, such as surface-active agents
(i.e., sodium laurylsulphate, polysorbate 80),
plasticizers (propylene glycol, polyethylene glycols, triacetin, triethylcitrate) , lubricants (talc) , opacizers and colouring agents (titanium dioxide, iron oxide) . The total thickness of the gastroresistant and protective films of the inventive pharmaceutical composition ranges between 100 and 180 μm, preferably 130-160 μm. Preferably, the pharmaceutical composition of the present invention comprises a derivative of partricin A and/or partricin B selected from the C1-C3 alkyl or aminoalkyl esters and amides thereof, optionally N'- acylated or amino-acylated. These partricin derivatives, optionally, can be used as such in the composition of the invention, or in a water- soluble form, obtained through salification with an acid (f.i. aspartic acid, ascorbic acid, glutammic acid) , or through complexation with a surface-active agent f.i., sodium laurylsulphate, sodium desoxycholate) . Mepartricin, mepartricin A, N' -dimethylamino-acetyl partricin A 2-pyridilethylamide and the mepartricin/sodium laurylsulphate complex are the partricin derivatives most preferably used in the composition of the invention. It is to be noted that the particular filmogenic combination of the present invention permits the preparation of pharmaceutical compositions, for example in the form of tablets resistant to the gastric juices, affording an unexpected long-term stability to the partricin derivatives and rapidly disintegrating in enteric environment, even after ageing at high temperatures.
The use of water too, as the main or even sole solvent or dispersant of the filmogenic agents during
application on the tablets, is not solely in function of making operations easier, less liable to the danger of fire and explosion, and not so polluting, but permits the preparation of pharmaceutical compositions in which the partricin derivatives are definitely stabler than those in which organic and/or chlorinated solvents were used to solubilize the filmogenic agents.
It was also unexpectedly observed that the partricin derivatives comprised in the composition of the invention, administered at doses (40-120 mg/die) sensibly higher than those presently used (26-39 mg/die) , lead to definitely better therapeutic results as regards both the symptomatology and the prostate size, even in patients with advanced BPH, who are commonly less sensitive to the present therapeutic doses of mepartricin.
This discovery not only helps alleviate discomfort in BPH patients but further reduces the need for surgery exactly in the cases in which it has become undeferable, owing to the gravity of the symptoms and the risk of complications.
Moreover, mepartricin was found able to bind not only with cholesterol but also with various androgen steroid hormones and, in particular, with estrogens, whose function in the cell stimulation process is known. The validity of the use of mepartricin in the preparation of a drug for the treatment of pathologies due to the umbalance of estrogens, generally hyperoestro-genaemia and those pathologies which may be correlated to such an umbalance, has been hypothyzed. Among such pathologies we have particularly considered benign prostatic hypertrophy whose etiology is likely to be found in the altered ratio of estrogens to androgens . It was shown that the foregoing binding capacity of mepartricin helps
elimination of the estrogens at intestinal level (increase of faecal excretion) since insoluble complexes are formed, decreases the circulating estrogen blood levels and reduces their biliary secretion (hence their enterohepatic recirculation) in correspondence with the main meals, with a circadian rhythm exhibiting its peak in the evening hours. For this reason a single daily administration of the total dose of mepartricin is preferable, to be given after the evening meal, or, at most, 2 daily administrations after the main meals and not 8-hourly as considered preferable in the documents coming before the present invention, supported also by mepartricin absence of oral toxicity. It was therefore found that better therapeutic results could be obtained with one single daily administration of the total dose of mepartricin, rather than with repeated daily doses, which not only favours patient's compliance, specially during long-term treatments but also reduces the risk of under- or overdosage due to posologic errors.
The following examples are given only with the purpose of better illustrating the invention, but in no way are they to be construed as limiting the scope of the invention itself . Example 1
Formula for gastroresistant tablets containing 40 m active ingredient:
£Ω££.:
Mepartricin 40 mg Starch 40 mg
Talc 5 mg
Magnesium stearate 2.5 mg
Lactose q.s. ad 280 mg
Gastroresistant film coating
Copolymer of methacrylic acid and of ethyl acrylate 13.2 mg
Triethylcitrate 2 mg
Polysorbate 80 0.3 mg Sodium laurylsulphate 0.1 mg
Talc 4.1 mg
Titanium dioxide 0.2 mg
Ferrous oxide 0.1 mg
Protective film coating Polyvinyl alcohol 13.3 mg
Pullulan 3.5 mg
Polyethylene glycol 6000 1.6 mg
Talc 1.6 mg
Preparation method Mix together the constituents of the core and compress the mixture using a compressing machine.
Disperse the constituents of the gastroresistant film coating in water (about 10 litres per 100,000 tablets) and spray-coat the cores in a coating pan. Dry the coated cores overnight in oven at 40°C.
Dissolve polyvinyl alcohol, pullulan and polyethylene glycol in water (about 30 litres per 100,000 tablets) , disperse talc therein and spray-coat the already gastroresistant cores in coating pan. Dry the finished tablets overnight at 40°C in oven.
Example 2
Formula for gastroresistant tablets containing 80 mg of active ingredient:
Core Mepartricin 80 mg
Starch 40 mg
Talc 5 mg
Magnesium stearate 2 . 5 mg
Lactose q.s. ad 280 mg
Gastroresistant film coating
Copolymer of methacrylic acid and of ethyl acrylate 13.2 mg
Triethylcitrate 2 mg Polysorbate 80 0.3 mg
Sodium laurylsulphate 0.1 mg
Talc 4.1 mg
Titanium dioxide 0.2 mg
Ferrous oxide 0.1 mg Protective film coating
Polyvinyl alcohol 13.3 mg
Pullulan 3.5 mg
Polyethylene glycol 6000 1.6 mg
Talc 1.6 mg Preparation method
Mix together the constituents of the core and dry- compound the mixture using an appropriate compounding machine; granulate, π.ir again and compress using a compressing machine. Disperse the constituents of the gastroresistant film coating in water (about 5 litres per 100,000 tablets) and spray-coat the cores in a coating pan. Dry the coated cores overnight in oven at 40°C.
Dissolve polyvinyl alcohol, pullulan and polyethylene glycol in water (about 30 litres per 100,000 tablets) , d-' sperse talc therein and spray-coat the already gastroresistant cores in coating pan.
Dry the finished tablets overnight at 40°C in oven.
Example 3 Formula for gastroresistant tablets containing 80 mg of active ingredient : Core
Mepartricin A 80 mg
Starch 40 mg
Talc 5 mg
Magnesium stearate 2.5 mg
Lactose q.s. ad 280 mg
Gastroresistant film coating Copolymer of methacrylic acid and of ethyl acrylate 13.2 mg
Triacetin 2 mg
Polysorbate 80 0.3 mg
Sodium laurylsulphate 0.1 mg Talc 4.1 mg
Titanium dioxide 0.3 mg
Protective film coating
Polyvinyl alcohol 6.7 mg
Dextrin 1.7 mg Tween 80 1.6 mg
Preparation method
Mix together the constituents of the core and dry- compound the mixture using an appropriate compounding machine; granulate, mix again and compress using a compressing machine.
Disperse the constituents of the gastroresistant film coating in water (about 10 litres per 100,000 tablets) and spray-coat the cores in a coating pan. Dry the coated cores overnight in oven at 40°C. Dissolve polyvinyl alcohol, dextrin and Tween 80 in water (about 15 litres per 100,000 tablets) , and spray- coat the already gastroresistant cores in coating pan.
Dry the finished tablets overnight at 40°C in oven.
Example 4 Formula for gastroresistant tablets containing 80 mg of active ingredient :
£o_r_e.
N ' -dimethylaminoacetyl partricin A
2 -pyridilethylamide 80 mg
Starch 40 mg
Talc 5 mg
Magnesium stearate 2.5 mg
Lactose q.s. ad 280 mg Gastroresistant film coating Copolymer of methacrylic acid and of ethyl acrylate 6 . . 6 mg Polyethylene glycol 400 1 mg Polysorbate 80 0 . . 15 mg Sodium laurylsulphate 0 . , 05 mg Talc 2 mg
Titanium dioxide 0 , . 2 mg Protective film coating
Hydroxypropylmethylcellulose 13.3 mg Dextrin 1.7 mg
Propylene glycol 1 mg
Talc 4 mg
Preparation method
Mix together the constituents of the core and dry- compound the mixture using an appropriate compounding machine; granulate, mix again and compress using a compressing machine.
Disperse the constituents of the gastroresistant film coating in water (about 5 litres per 100,000 tablets) and spray-coat the cores in a coating pan. Dry the coated cores overnight in oven at 40°C.
Dissolve hydroxypropylmethylcellulose dextrin and propylene glycol in water (about 30 litres per 100,000 tablets) ,therein disperse talc, and spray-coat the already gastroresistant cores in coating pan.
Dry the finished tablets overnight at 40°C in oven.
Example 5
Tablets prepared with 4 different formulations of mepartricin were stored in aluminium/aluminium blisters
at 37°C and re-controlled for gastroresistance, disintegration time and titre of the active ingredient after 6 months.
The formulations had the following characteri-stics : Formula I : 40-mg cores, like those in example 1, but coated with a gastroresistant film coating made up of cellulose acetophthalate dissolved in isopropyl alcohol and ethyl acetate and with a protective film coating made up of hydroxypropylmethylcellulose dissolved in isopropyl alcohol and chloroform.
Formula II : 40-mg cores, like those in example 1, but coated with a gastroresistant film coating made up of cellulose acetophthalate, rendered water-soluble through salification with ammonia and dissolved in water, and with a protective film coating made up of hydroxypropyl¬ methylcellulose dissolved in water.
Formula III : 40-mg cores, likethose described in example 1, but coated with a gastroresistant film coating only, made up like that in example 1. Formula IV : 40-mg cores, like those in example 1, coated with both the gastroresistant film coating of example 1, and by the protective film coating again of example 1. The following table reports the results obtained:
Long-term stability at 37°C of mepartricin gastroresistant tablets
Formula I II III IV
Time Starting 6 mos Starting 6 mos Starting 6 mos Starting 6 mos
Gastroresistance Regular Regular Regular Regular Regular Regular Regular Regular
(according to EP)
Disintegration 33' 35' 16 >60' 5' 7' 5' 5'
Titre 100% 84% 100% 92% 100% 83% 100% 99%
Comparison between formula I and formula II evidences well the negative effect of the solvents on mepartricin chemical stability.
Formula II presents fair stability of the active ingredient but unsatisfactory disintegration of the tablets following accelerated ageing.
Formula III solves the problem of disintegration of the tablets to the detriment however of mepartricin stability. Formula IV alone concomitantly and brilliantly solves the problems of gastroresistance, disintegration and chemical stability of the active ingredient.
Example 6
Three groups of 10 patients each underwent double-blind treatment with mepartricin for 3 months according to the following treatment scheme:
Group I : mepartricin three 50,000 U (13 mg) tablets daily (8-hourly) for a total of 39 mg of mepartricin daily (US patent no. 4,237,117). Group II : mepartricin two 40-mg tablets (formula of example 1) daily, following the main meals for a total of 80 mg daily.
Group III : mepartricin one 80-mg tablet daily (formula of example 2) following the evening meal. Before and after trial the following symptoms were recorded: pollakiuria, nocturia, force and caliber of stream, prostate size at transrectal echotomography. The following table reports the results obtained:
The table shows that treatment was more effective in group II (40 mg x twice daily) and group III (80 mg daily) , as compared to group I (13 mg x 3 times daily) , with slight preference for group III against group II. It is to be noted that no side effects occurred in any of the groups and that no significant changes were observed in the biohumoral parameters. Example 7
To further demonstrate the capacity of binding 17β- estradiol, suspensions of mepartricin in 0,5% carboxymethyl cellulose were incubated with 0,5 μCi of 14C-estradiol (specific activity 54.1 mCi/mmole) at 37°C for 1 hour with continuous shaking in a total volume of
2 ml . At the end of the incubation period the suspensions were centrifuged for 15 min at 14000 rpm and the radioactivity in the supernatants were analyzed. Two concentrations of mepartricin were tested: 1 and 3 mg/ml . A suspension of only carboxymethyl cellulose served as control. The tests were performed in duplicate .
In additional tests, 14C-estradiol (0,5 μCi) was incubated with bile and plasma obtained from untreated rats, for 1 hour at 37°C, in absence and presence of mepatricin in a total volume of 1 ml . At the end of the incubation period the samples were centrifuged and the radioactivity in supernatant was determined. Two mepartricin concentrations were tested: 1 and 3 mg/ml. The following table reports the results of the in vitro binding study of 14C-estradiol to mepartricin in vehicle
(0.5% carboxymethyl cellulose) , in rat bile and in rat plasma. In vehicle, the precipitable radioactivity was lβ% in the presence of 1 mg/ml of mepartricin and 41% i .r 3 mg/ml. In bile, 20% of radioactivity precipitated in absence of mepartricin, but this figure increased to 43% in presence of 1 mg/ml of mepartricin and 67% for 3 mg/ml. In rat plasma 9% precipitated in the absence of mepartricin, 33% at a mepartricin concentration of 1 mg/ml and 46% at 3 mg/ml.
These experiments demonstrate that mepartricin binds 14C- estradiol to form insoluble complexes and this binding occurs both in aqueous solutions and in biological matrices. Based on these data, the increase of faecal excretion of orally administered 14C-estradiol in in vivo tests (data not shown) , seems to be chemico-physical rather than a biological process.
In vitro binding of 14C, -estradiol to mepartricin in different matrices.
CMC = carboxymethylcellulose dpm/ml = degradation per minute
Claims
1. A pharmaceutical composition comprising a polyene derivative as the active ingredient, an inner gastroresistant film coating comprising a copolymer of methacrylic acid and ethyl acrylate, and an outer protective film coating comprising a water-soluble polymer and a polysaccharide, where the ratio between the gastroresistant film coating and the protective film coating ranges from 4:1 to 1:4 and where the quantity of the said films makes up the 2 to 20% of the final weight of the pharmaceutical composition.
2. A pharmaceutical composition according to claim 1, wherein the water-soluble polymer is selected in the group formed by a cellulose derivative such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellu-lose, hydroxyethylcellulose, and by a polyvinyl derivative such as polyvinyl alcohol and polyvinylpyrrolidone.
3. A pharmaceutical composition according to claim 1, wherein the polysaccharide is selected in the group formed by dextrin, dextran and pullulan.
4. A pharmaceutical composition according to claim 1, wherein the total thickness of the gastroresistant and protective films ranges between 100 and 180 μm, preferably 130-160 μm.
5. A pharmaceutical composition, according to claim 1, wherein the ratio between the gastroresistant film coating and the protective film coating ranges from 2:1 to 1:2.
6. A pharmaceutical composition according to any of the foregoing claims, comprising moreover, at least one adjuvant of the manufacturing process, selected in the group of the sodium laurylsulphate, polysorbate 80, propylene glycol, polyethylene glycol, triacetin, triethylcitrate, talc and titanium dioxide and/or iron oxides.
7. A pharmaceutical composition according to any of the foregoing claims, wherein the solvent or dispersant used in the application of the film coatings is water.
8. A pharmaceutical composition according to any of the foregoing claims, wherein the polyene derivative is a derivative of partricin A and/or B selected among the C1-C3 alkyl or aminoalkyl esters and amides thereof, optionally N'-acylated or aminocylated and/or in the water-soluble form.
9. A pharmaceutical composition according to claim 8, comprising 40-120 mg of the partricin derivative.
10. A pharmaceutical composition according to claim 8 or 9, wherein the partricin derivative is mepartricin, mepartricin A or N' -dimethylamino-acetyl partricin A-2- pyridilethyl-amide.
11. A pharmaceutical composition according to any of the foregoing claims 8 to 10, wherein the partricin derivative is salified with an acid substance or complexed with a surface-active agent.
12. A pharmaceutical composition according to claim ,11/ wherein the partricin derivative is the mepartricin/sodium laurylsulphate complex.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97921711A EP0946187A1 (en) | 1996-06-12 | 1997-04-23 | Coated compositions containing polyene derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI96A001191 | 1996-06-12 | ||
| IT96MI001191A IT1283124B1 (en) | 1996-06-12 | 1996-06-12 | PHARMACEUTICAL FORMS AND COMPOSITIONS FOR THE TREATMENT OF BENIGN PROSTATIC HYPERTROPHY |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997047311A1 true WO1997047311A1 (en) | 1997-12-18 |
Family
ID=11374410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1997/002056 WO1997047311A1 (en) | 1996-06-12 | 1997-04-23 | Coated compositions containing polyene derivatives |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0946187A1 (en) |
| IT (1) | IT1283124B1 (en) |
| WO (1) | WO1997047311A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049270A2 (en) * | 1999-12-30 | 2001-07-12 | Ancile Pharmaceuticals, Inc. | Odor-masking coating for a pharmaceutical preparation |
| US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| US11370753B2 (en) | 2017-12-05 | 2022-06-28 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US11517558B2 (en) | 2017-12-05 | 2022-12-06 | Sunovion Pharmaceuticals Inc. | Nonracemic mixtures and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4237117A (en) * | 1979-10-05 | 1980-12-02 | Spa-Societa Prodotti Antibiotici S.P.A. | Method for the treatment of benign prostatic hypertrophy |
| JPH0770506A (en) * | 1993-09-07 | 1995-03-14 | Morishita Roussel Kk | Film coating composition and solid pharmaceutical preparation made by using it |
-
1996
- 1996-06-12 IT IT96MI001191A patent/IT1283124B1/en active IP Right Grant
-
1997
- 1997-04-23 EP EP97921711A patent/EP0946187A1/en not_active Withdrawn
- 1997-04-23 WO PCT/EP1997/002056 patent/WO1997047311A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4237117A (en) * | 1979-10-05 | 1980-12-02 | Spa-Societa Prodotti Antibiotici S.P.A. | Method for the treatment of benign prostatic hypertrophy |
| JPH0770506A (en) * | 1993-09-07 | 1995-03-14 | Morishita Roussel Kk | Film coating composition and solid pharmaceutical preparation made by using it |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE WPI Week 9519, Derwent World Patents Index; AN 95-145068 [19], XP002035958 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001049270A2 (en) * | 1999-12-30 | 2001-07-12 | Ancile Pharmaceuticals, Inc. | Odor-masking coating for a pharmaceutical preparation |
| WO2001049270A3 (en) * | 1999-12-30 | 2002-01-03 | Ancile Pharmaceuticals Inc | Odor-masking coating for a pharmaceutical preparation |
| US6419956B1 (en) | 1999-12-30 | 2002-07-16 | Ancile Pharmaceuticals | Odor-masking coating for a pharmaceutical preparation |
| US6667059B2 (en) | 1999-12-30 | 2003-12-23 | Ancile Pharmaceuticals, Inc. | Odor-masking coating for a pharmaceutical preparation |
| US11370753B2 (en) | 2017-12-05 | 2022-06-28 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US11517558B2 (en) | 2017-12-05 | 2022-12-06 | Sunovion Pharmaceuticals Inc. | Nonracemic mixtures and uses thereof |
| US11767293B2 (en) | 2017-12-05 | 2023-09-26 | Sunovion Pharmaceuticals Inc. | Crystal forms and production methods thereof |
| US11160758B2 (en) | 2019-06-04 | 2021-11-02 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
| US11654113B2 (en) | 2019-06-04 | 2023-05-23 | Sunovion Pharmaceuticals Inc. | Modified release formulations and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI961191A1 (en) | 1997-12-12 |
| EP0946187A1 (en) | 1999-10-06 |
| ITMI961191A0 (en) | 1996-06-12 |
| IT1283124B1 (en) | 1998-04-07 |
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