FR2598614A1 - Osmotic system for the controlled supply of haloperidol - Google Patents

Abstract

The invention relates to an osmotic system for the controlled supply of haloperidol to a medium for its application at a controlled rate over an extended period of time. The system is made in the form of a device 10 containing a semi-permeable wall 14 which surrounds and defines a compartment 15 in which haloperidol is present in combination with a di- or tricarboxylic acid which increases the solubility of the haloperidol and facilitates its release via a passage 12. Field of application: haloperidol therapy.

Description

 The present invention relates to the controlled supply of a therapeutically useful quantity of haloperidol by an osmotic supply system. The invention also relates to a method for solubilizing haloperidol as well as an improved method for producing a therapeutic effect by administration of the solubilized haloperidol.

 Haloperidol, which is 4- (4- (p-chlorophenyl) - 4-hydroxy-1-piperidinyl] -1- (4-fluorophenyl) -1-butanone, is a tranquilizer indicated for the treatment of manifestations of disorders Haloperidol is particularly indicated as a neuroleptic useful in the treatment of acute and chronic schizophrenia.

 At present, haloperidol is available as conventional tablets. These unmeasured dosage tablets containing 0.5 mg to 2.0 mg of haloperidol are given two or three times a day to patients with moderate symptoms, and tablets of the same type containing 3.0 mg to 5.0 mg of haloperidol are also administered two or three times a day to patients with severe symptoms.

 The duration of drug release from these conventional dosage forms is almost instantaneous, or at best a few hours. This short period of drug release has at least two adverse effects. The first is that it is necessary to carry out frequent administrations which lead to a lack of observance of the dosage regimens by the patient. What is associated with this failure is not only the loss of efficiency of administration, but also a possible accentuation of undesirable side effects which results from the fact that the patients increase their doses to compensate for the previous omissions. adverse effect is that discontinuous periodic administration almost inevitably leads to the appearance of a peak drug level which exceeds the level required at the time of administration, and then to a decline in the drug level which drops below the level required to achieve the desired therapeutic effect.

 It is clear from the above that there is a critical and urgent need for a dosage form which can deliver haloperidol at a controlled rate and continuously over an extended period of time. This need exists for haloperidol since the prior art has not provided a controlled release dosage form suitable for haloperidol, and because its physical and chemical properties do not lend themselves to dosage forms controlled release. Indeed, haloperidol is sensitive to light, non-hygroscopic and practically insoluble in water, properties which are ill-suited to controlled release dosage forms.

Therefore, a first object of the present invention is to provide an osmotically controlled release dosage form which makes a contribution to pharmaceutical administration techniques in that it makes it possible to deliver haloperidol at a controlled and continuous rate over an extended period of time
Another object of the present invention is to provide an improvement to haloperidol therapy by providing an osmotic delivery system which contains haloperidol in a solubilized form for its sustained and sustained release during the time.

 Another object of the present invention is to provide an osmotic delivery system for the controlled release of haloperidol in a manner suited to its bioavailability and to its pharmacokinetic effects by taking once a day.

 Yet another object of the invention is to provide an improved therapeutic method for the administration of haloperidol, which method comprises administering haloperidol at a regulated rate of release over an extended period of time to a patient who has it need.

 Yet another object of the invention is to provide an osmotic system comprising a compartment containing haloperidol maintained in a very soluble state to promote a substantially complete supply to a warm blood recipient.

These and other objects of the present invention will become more apparent from the following description and the accompanying drawings in which
Figure 1 shows an embodiment of an osmotic supply device according to the invention;
Figure 2 shows the device of Figure 1 in open section
Figure 3 shows another embodiment of a device according to the invention; and
FIGS. 4 to 7 are graphs representing the rates of release and the cumulative amounts released of haloperidol by osmotic delivery devices produced in the examples below.

 The present invention is based on the discovery that haloperidol can be administered from an osmotic delivery system over an extended period of time.

Before the present invention, haloperidol could not be delivered by an osmotic supply device because it is practically insoluble in water, its solubility being less than 0.1 mg / ml, and because it manifests a pressure almost zero osmotic. We have now unexpectedly discovered that haloperidol can be successfully delivered by an osmotic device thanks to a notable increase in the solubility of haloperidol produced by mixing the latter with a saturated or unsaturated dicarboxylic or tricarboxylic acid, C2 to C4 and, in one embodiment, with hydroxydicarboxylic, hydroxytricarboxylic or dihydroxydicarboxylic acids C2 to C4. Representative examples of dicarboxylic and tricarboxylic acids include citric acid, maleic acid, malic acid, dihydroxysuccinic acid and mixtures thereof. In one embodiment, the invention further uses succinic acid as mixture with at least one acid chosen from citric acid, maleic acid.

and malic acid. For example, haloperidol mixed with citric acid becomes very soluble and has a solubility of 165 mg / ml; in the presence of haloperidol, citric acid has a solubility of 555 mg / ml, and the total solubility of the mixture of haloperidol and citric acid is 720 mg / ml in aqueous solution. The equilibrium ratio, found to a measure, of citric acid to haloperidol for a mutually saturated solution is 3.4 to 1. The invention generically encompasses a ratio of citric acid to haloperidol ranging from 3 parts of citric acid per 1 part of haloperidol up to 100 parts of citric acid per 1 part of haloperidol, the parts being expressed by weight. In a presently preferred embodiment, the ratio of acid carboxylic to haloperidol ranges from 3 parts of carboxylic acid for one part of haloperidol to 100 parts of carboxylic acid to 1 part of haloperidol, such as citric acid to haloperidol ratios of 46 to 1, 20 to 1, 16 to 1, 12 to 1 and 8 to 1. The mutually saturated solution comprising haloperidol and citric acid has an osmotic pressure of 150 atmospheres at the ratio 3.4. Haloperidol mixed with maleic acid has an increased solubility of more than 200 mg / ml in aqueous solution, and haloperidol mixed with maleic acid has an increased solubility of more than 250 mg / ml in solution saturated aqueous haloperidol and malic acid. The mutually generated properties of high solubility and high osmotic pressure lead to the manufacture of an osmotic device which can successfully deliver haloperidol at a controlled rate over an extended period of time.

 The haloperidol is delivered by an osmotic device comprising a wall which surrounds and defines a compartment. The compartment contains both a dosage amount of haloperidol and di- or tricarboxylic acid.

The compartment optionally contains pharmaceutical ingredients used to facilitate manufacture and regulate release.

The wall of the osmotic delivery device consists of a semipermeable composition which does not adversely affect haloperidol, di- or tricarboxylic acid or a biological host. The wall consists of a semipermeable composition which is permeable to an external liquid, such as water and biological liquids, and substantially impermeable to haloperidol, to di- or tricarboxylic acid and to the other ingredients present in the compartment.Polymers with selective permeability useful for manufacturing the osmotic device are represented by a non-toxic material chosen from the following pharmaceutically acceptable materials: cellulose ester, cellulose diester, cellulose triester, cellulose ether, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate and cellulose acetate butyrate. Suitable polymers useful for making osmotic devices are described in US Pat. Nos. 3,845,770; 3,916,899; 4,008,719 4,036,228 and 4,111,210, all transferred to ALZA Corporation of
Palo Alto, California, assignee of this application.

In one embodiment, the wall of the osmotic device can be a laminate comprising a semipermeable layer in laminar arrangement with a microporous layer. The semipermeable layer consists of the above polymers. The microporous layer comprises several micropores and microchannels linked together to allow the external liquid to enter the device. The microporous layer can consist of the above polymers containing a pore-forming agent which is dissolved, or leached from the layer, when the osmotic device is active in the biological environment of use. The blowing agents are non-toxic and they do not react with the materials constituting the laminated wall. Upon their elimination from the layer, the channels formed fill with liquid and these channels become a path taken by the liquid to enter the device, in cooperation with the semipermeable layer. Typical blowing agents are represented by sodium chloride, potassium chloride, sorbitol, mannitol, polyethylene glycol, hydroxypropyl methyl cellulose and hydroxypropylbutyl cellulose. Osmotic delivery devices comprising a laminated wall comprising a semipermeable layer and a microporous layer are described in the patent for
EUA N 4,160,452, transferred to ALZA Corporation. In another embodiment, the exterior surface of the osmotic device can be coated with a non-toxic coating containing a non-toxic and water-soluble dye.

The coating can be applied to the semipermeable wall or to the laminated wall. For example, the coating may consist of hydroxypropyl methyl cellulose mixed with a yellow aluminum lacquer which is pharmaceutically acceptable (Food, Drug and Cosmetic) as a colorant.

The term "passage" as used herein for an osmotic device includes an opening, an orifice, a hole and the like made through the wall and sized for osmotic activity. This term also includes an erodible element placed in the wall, for example a gelatin plug which erodes in the environment of use by creating an osmotic passage A detailed description of osmotic passages, and of the maximum and minimum dimensions which suit them, can be found in the patents of
EUA N 3,845,770 and 3,916,899, sold to ALZA Corporation.

 The amount of haloperidol contained in the osmotic device is a function of the therapeutic reaction sought in the biological environment of use. In general, the device contains 0.1 mg to 250 mg of haloperidol, individual devices containing for example 0.5 mg, 2.0 mg, 3.0 mg, 10.0 mg, 100 mg, etc. Generally the osmotic device contains 0.3 mg to 750 mg of the di- or tricarboxylic acid, individual devices containing 0.3 mg, 1.5 mg, # 6.0 mg, 9.0 mg , 30.9 mg, 300 mg, etc. Haloperidol and carboxylic acid can be found in various forms in the compartment of the osmotic device, for example in the dry and solid form of granules, powder, compressed mass, film and the like. the carboxylic acid may be present in the compartment in admixture with a binder, a dye, a lubricant, a dispersant, and other pharmaceutical pharmaceutical ingredients. Haloperidol is a drug well known in pharmacy, as described in Remington's Pharmaceutical Sciences, 14th edition, page 1108, 1970, published by Mack Publishing Company, Easton, Pennsylvania.

 The pharmaceutical manufacturing ingredients include binders such as poly (ethylene glycol), gelatin, agar, carboxy-cellulose, polyvinyl alcohol and polyvinylpyrrolidone. Typical lubricants include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, halogenated vegetable oils and talc. The compartment can also contain a disintegrant to cause dissolution and form a solution of haloperidol and citric acid in order to improve the controlled supply from the osmotic device. Typical disintegrants include lightly crosslinked polyvinylpyrrolidone, mals starch, potato starch, Veegum @, bentonite and citrus pulp. Coloring agents include non-toxic coloring agents approved by Food, Drug and Cosmetic such than Blue N0 1 in lactose. The colorant of the compartment and that of the wall can optionally be identical or different. The amount of binder, lubricant or disintegrant is usually about 0.1 mg to 20 mg for each.

 The osmotic devices provided by the present invention, containing haloperidol and di- or tricarboxylic acid, are manufactured by conventional manufacturing techniques. For example, in one embodiment, the haloperidol is mixed with the carboxylic acid improving the solubility of the haloperidol, and with the other core ingredients constituting the compartment, by ball milling, calendering, agitation, and the ingredients are compressed into a predetermined shape corresponding to the shape of the final osmotic device. The material constituting the wall of the device can be applied by dipping> molding or spraying on the compressed mixture. One technique for applying the semi-waterproof wall is the technique of coating in a fluidized air bed, which can be use to make a wall formed of a single layer or of several layers and which is described in the US patent NO 2,799,241; J. Am. Pharm. Assoc., Vol. 48, pages 451 to 459, 1959 ~ and ibid., Vol 49, pages 82 to 84, 1960. An osmotic passage is performed by mechanical drilling, laser drilling, punching or die cutting. A method of forming the passage using a laser is described in the U.S. Patents. Nos. 3,916,899 and 4,088,864, sold to ALZA Corporation. An osmotic delivery device suitable for oral administration can have various shapes and sizes. It can for example be round and have a diameter of 4.76 to 14.28 mm, or it can have the shape of a full capsule in a range of models from triple zero to zero and from 1 to 8. Under these forms, the osmotic device is sized, shaped and adapted to the administration of haloperidol to warm-blooded animals, this expression encompassing human beings.

Other conventional manufacturing techniques are described in Modem Plastic Encyclopedia, Vol. 46, pages 62 to 1969; Remington Pharmaceutical Sciences, 14th edition, pages 1649 to 1698, 1980; and The Therapy and Pratice of
Industrial Pharmacy, de Lackmann et al., Pages 197 to 225, 1970, published by Lea & Febiger Co., Philadelphia, Pennsylvania.

 The following nonlimiting examples illustrate the present invention.

Example 1
A therapeutic osmotic device for the gentle and continuous supply of haloperidol as a profitable drug is produced as follows: First, pass through a 0.250 mm sieve 28.35 g of haloperidol, 444.15 g of citric acid anhydrous, 10.00 g of polyvinylpyrrolidone and 10.00g of crosslinked Povidone, and the whole is mixed in a V-mixer for 1 hour. The mixed ingredients are then transferred to a larger mixer, a granulation liquid consisting of an ethanol: water mixture at 90:10 by volume is added to the mixer and the mixture is mixed for 20 minutes. The ingredients are then mixed homogeneously through a 0.59 mm sieve and dried in an forced air oven for 16 hours at 50 C.

 After drying, the granules are passed through a 0.84 mm sieve and 7.5 g of stearic acid are added to them. All ingredients are mixed for 15 minutes. The granules are transferred to a Manesty tablet press and compressed to obtain concave cores of 8 mm, 176 mg, which constitute drug reserves.

 The haloperidol reserves are transferred to an Aeromatic ~ fluidized air bed coating machine and a film consisting of cellulose acetate having an acetyl group content of 39.8% is applied around the drug cores. The semipermeable film is applied around the reserves from a composition composed of 33 g of cellulose acetate dissolved in a solvent consisting of 510 ml of methylene chloride and 105 mol of methanol. After having formed the semipermeable film around the reserves, they are transferred to an forced air oven and dried for 48 hours at 50 ° C.

An osmotic passage 0.36 mm in diameter is then pierced by laser in the semipermeable wall. The semipermeable wall weighs 13.5 mg and is 0.13 mm thick. The ratio of haloperidol to citric acid is 1: 15.7.

 The osmotic devices for the therapeutic supply of haloperidol prepared according to the present example are illustrated in FIGS. 1 and 2. In FIG. 1, there is shown an osmotic device 10 comprising a body 11 with a passage 12 which connects the exterior and the interior of the osmotic device 10. In FIG. 2, the osmotic device 10 is seen in open section at 13, and it comprises a semipermeable wall 14 which surrounds and defines an internal compartment 15. The compartment 15 contains the haloperidol 16, citric acid 17 and other pharmaceutical ingredients. Figure 4 shows the rate of release of haloperidol from the osmotic device. In Figure 4, the release rate is measured for the first 4 hours in artificial gastric juice, and for the next 8 hours in artificial digestive juice. Figure 5 shows the cumulative amount of haloperidol delivered in a period of 12 hours.

Example 2
An osmotic device which delivers haloperidol independently of the pH of the biological medium is shaped, dimensioned and manufactured as follows for administration by the oral route into the gastrointestinal tract: First of all, 22.5 g of haloperidol are mixed, 450 g anhydrous citric acid, 8.75 mg of non-crosslinked Povidone and 8.75 mg of
Povidone crosslinked, passes them through a 0.250 mm stainless steel sieve and mixes them for 1 hour at room temperature. The mixed ingredients are then transferred to a large mixer, 40 ml of a granulation liquid consisting of an ethanol: water mixture at 90:10 by volume are added to the mixer, and the ingredients are mixed for 20 minutes. the ingredients intimately mixed in the 0.59 mm sieve and dried in an forced air oven for 16 to 17 hours at 50 C.

 The dried granules are then passed through a 0.84 mm sieve and 10.0 mg of magnesium stearate are added to them.

The ingredients are mixed for 15 minutes and the mixed granules are transferred to a conventional Manesty press.

The ingredients are compressed to obtain haloperidol reserves each weighing 225 mg, containing 10 mg of haloperidol and having a ratio of haloperidol to citric acid from 1 to 20. The diameter of the compressed drug cores is about 8.1 mm.

 The compartment-forming compositions containing the haloperidol are transferred to a coating machine in a fluidized air bed and surrounds them with a semipermeable wall. The semipermeable wall is formed from a wall forming composition composed of 35 g of cellulose acetate having an acetyl group content of 39.8% and an organic solvent consisting essentially of 550 ml of methylene chloride and 110 ml of methanol. After having formed the semipermeable wall surrounding the reserve of medicament, the coated cores are dried in a forced air oven for 50 hours at 50 C. A 0.4 mm passage is then drilled in the semipermeable wall which connects the internal and external compartment of the osmotic device. Each osmotic device manufactured in accordance with this example weighs approximately 233.6 mg. The haloperidol supply weighs 225 mg and includes 4.5% haloperidol, 90% citric acid9 1.75% uncrosslinked Poviw done, 1.75% crosslinked Povidone and 2% magnesium stearate. The semipermeable wall weighs 8.6 mg.

The average rate of release of haloperidol from the osmotic device is approximately 0.83 mg / h over a 12 hour period. The cumulative release speed is shown in Figure 6 where the bars indicate the maximum and minimum release speeds of 6 values recorded at the time of measurement.

Example 3
The procedure of Example 2 is repeated with the manufacturing techniques described above, with the difference that in the present example the drug reserve weighs 44.9 mg and comprises 2 mg of haloperidol and that the semipermeable acetate wall of cellulose weighs 4.4 mg.

The osmotic passage measures 0.35 mm, and the device delivers haloperidol for 12 hours.

Example 4
The procedure of Example 2 is repeated, applying all the conditions previously described, except that in the present example the starting charge comprises 10 g of haloperidol, 462.5 g of anhydrous citric acid, 8.75 g of uncrosslinked Povidone, 8.75 g of crosslinked Povidone and 10 g of magnesium stearate. The final osmotic device comprises a haloperidol reserve weighing 100 mg which contains 2 mg of haloperidol at a ratio of haloperidol to citric acid of 1:46, and a semipermeable wall of cellulose triacetate which weighs 9.2 mg.

The osmotic passage measures 0.4 mm and the device delivers haloperidol for 12 hours.

Example 5
The procedure of Example 2 is repeated by applying all the conditions previously described, with the difference that in the present example haloperidol and citric acid are present in a ratio of 1 to 100.

 The final osmotic device has a passage of 0.36 mm, and the compartment weighs 214 mg and contains 0.94 ~% of haloperidol, 93.6% of citric acid, 1.75% of non-crosslinked Povidone, 1, 75% of crosslinked Povidone and 2% of magnesium stearate. The semipermeable wall weighs 14 mg. The release rate of haloperidol in mg / h is shown in Figure 7.

Example 6
An osmotic device for oral use for the administration of haloperidol to a patient in need is manufactured as follows: A composition of haloperidol is prepared to be housed in the compartment of the osmotic device by intimately mixing 15 mg of haloperidol base, 100 mg of maleic acid, 5 mg of gelatin, 3 mg of corn starch and 3 mg of stearic acid, then compressing the homogeneous mixture into a drug composition having the shape of the compartment. The compressed drug composition is then placed in a fluidized air bed coating machine and coated with a microporous layer forming composition. The microporous layer composition consists of 49% by weight of cellulose acetate having an acetyl group content of 39.8%, 28.5% by weight of hydroxypropylmethyl cellulose and 22.5% by weight of polyethylene glycol 4000. The layer is formed from a layer solvent which is a mixture of methylene chloride: ethanol at 80:20 by weight. The microporous layer has a thickness of 0.14 mm.

 An outer semipermeable layer is then applied to the microporous layer, in a conventional machine for coating in a fluidized air bed. The waterproofing composition consists of 90% by weight of cellulose acetate having an acetyl group content of 39.8% and 10% by weight of cellulose acetate having an acetyl group content of 32%. The semipermeable layer is applied in a laminar arrangement from a solvent mixture consisting of methylene chloride and 95% ethanol at 80:20 by weight. The osmotic devices are dried and a 0.26 mm diameter passage is pierced in the laminated wall by laser. The active device releases haiperidol in the stomach and in the intestine for its tranquilizing effect. In FIG. 3, there is shown such an osmotic device 10 with an open section at 13. The device 10 comprises a body 11 , a passage 12, an internal compartment 15 containing the haloperidol 16 and the maleic acid 18. The laminated wall of the device 10 comprises an internal microporous layer 19 in laminar arrangement with an external semipermeable layer 20.

Example 7
An osmotic device for oral use for the gentle and continuous supply of haloperidol is prepared according to the general procedure described above. In the osmotic device of the present example, the compartment houses a drug composition comprising 20 mg of haloperidol, 75 mg of malic acid, 4 mg of dextrose, 2 mg of potato starch and 3 mg of magnesium stearate.

After compression, the composition has a diameter of 9 mm.

The device comprises a laminated wall comprising an internal semipermeable wall essentially consisting of 60% by weight of cellulose acetate having an acetyl group content of 43.5% and a degree of substitution of 3, and 40% by weight of cellulose acetate having an acetyl group content of 39.8% and a degree of substitution of 2.4. The semipermeable layer is applied from a solvent consisting essentially of a mixture of methylene chloride and methanol at 80:20 by weight. The device comprises an external microporous layer essentially consisting of 55% by weight of cellulose acetate having an acetyl group content of 39.8 aO, 35% by weight of sorbitol and 10% by weight of polyethylene glycol 400. is applied from a solvent consisting of a mixture of methylene chloride-methanol-water at 26: 35: 3 by weight. The semipermeable layer is 0.12 mm thick and the microporous layer is 0.13 mm thick. The device has a 0.25 mm passage.

Example 8
An osmotic therapeutic device for the gentle and continuous supply of haloperidol is prepared according to the procedure of Example 1, applying all the conditions described, except that the compartment contains an excess of citric acid and of acid. succinic, in an amount of 400.15 g # of citric acid per 44 g of succinic acid.

 In its currently preferred embodiments, the invention relates to (1) a method for treating psychotic disorders in a patient with such conditions; (2) a method for tranquilizing a patient who needs it; and (3) a method for treating hyperactivity in a human patient suffering from hyperactivity, which method (1), (2) or (3) consists in administering to the patient haloperidol as a beneficial drug and is characterized in that that it comprises the stages according to which: (A) a suitable, shaped and dimensioned osmotic device is admitted orally into the gastrointestinal tract of the patient, the osmotic device comprising: (a) a wall made of a semipermeable composition non-toxic which is permeable to an external liquid and substantially impermeable to haloperidol (b) a compartment, surrounded and defined by the wall, which contains a unit dosage amount of haloperidol and an effective amount of citric acid to increase solubility haloperidol and its ability to be released from the osmotic device; and (c) a passage made in the wall to put the exterior of the osmotic device in communication with the interior of this osmotic device; (B) an external liquid is absorbed in the compartment through the semipermeable wall at a speed determined by the permeability of the semipermeable wall and the osmotic pressure gradient exerted on either side of the semipermeable wall, to form a solution containing haloperidol and citric acid which is released from the osmotic device by hydrodynamic and osmotic effects; and (C) haloperidol is delivered by the passage to the patient's gastrointestinal tract in a therapeutically effective amount at a rate continuously adjusted to produce the desired profitable effect over an extended period of time. The method of the invention also comprises an improvement according to which the compartment contains haloperidol and maleic acid, or haloperidol and malic acid, or haloperidol and citric acid and succinic acid, and the beneficial drug is delivered at a regulated rate and continuously over a period of time from 15 minutes to 24 hours, in a therapeutically effective amount which is sufficient to produce the desired therapeutic effect in a warm-blooded animal that needs it.

 The invention provides a therapeutic osmotic system fabricated as an osmotic device containing haloperidol, and an improved method of haloperidol therapy. It goes without saying that the invention is not limited to the embodiments described and shown and that it is possible to make various modifications to it without going beyond its ambit.

Claims (1)

CLAIM  1. Osmotic system for the gentle supply of haloperidol to a medium of use, characterized in that it comprises  (a) a wall (14; 20) made of a composition permeable to an external liquid and substantially impermeable to haloperidol  (b) a compartment (15) containing a dosage amount of haloperidol (16) and an effective amount of an acid (17; 18) selected from citric acid, malic acid and maleic acid to increase the solubility of haloperidol thereby improving the release of haloperidol; and  (c) at least one passage (12) passing through the wall, which puts the outside of the system in communication with the inside of the system to release the haloperidol at a rate adjusted over time.