HRP970004A2 - Pharmaceutically controlled release of beads comprising furosemide and a formulation containing said controlled release beads - Google Patents

Description

The field of invention

The present invention relates to a pharmaceutical controlled release of particles containing furosemide and a preparation containing said particles with controlled release suitable for the treatment of cardiovascular diseases, such as mild and moderate hypertension, congestive heart attack and edema. The preparation has beneficial release properties according to the usual dosage forms, thereby providing an attractive dosage form without unpleasant side effects, for the long-term treatment of hypertension with furosemide.

Background of the invention

Medical treatment of certain physiological conditions, for example, high blood pressure, often requires continuous treatment over a long period of time, and the patient is often subjected to lifelong treatment, which requires a simple and suitable dosage regimen with regard to ease of administration and an acceptable level of side effects. High blood pressure is often treated with diuretics, for example, furosemide. Furosemide is a diuretic that is preferably used in the long-term treatment of cardiac edema, or mild to moderate edema. However, furosemide is also used to treat mild to moderate hypertension, especially when kidney function is reduced, or diabetes. Furosemide is also used in case of congestive heart attack.

Furosemide is an acid with a pKa value of 3.9 and furosemide is normally characterized (USP XXIII) as practically insoluble in water, soluble in acetone and in alkaline aqueous solutions, which means that furosemide exhibits pH-dependent solubility.

Administering furosemide orally, in the usual dosage form, results in an immediate and significant diuretic effect in the first hours after administration. The use of furosemide for the treatment of hypertension therefore adds special requirements to the furosemide preparation with regard to the rapid occurrence of urination caused by the substance itself. In order to reduce the rapid onset of micturition caused by furosemide, a controlled-release preparation must be prepared to provide a reduced initial micturition while at the same time maintaining an antihypertensive effect. This means that the release of furosemide from a sustained-release dosage form must be balanced between the disadvantage of an immediate increase in urination after oral administration and the advantage of furosemide-induced reduction in blood pressure in humans.

Therefore, it is highly desirable to have a furosemide preparation with controlled release, intended for the treatment of elevated blood pressure, with a uniform urination cross-section and a small total urination. It is therefore an object of the present invention to provide a controlled release composition comprising furosemide, suitable for the treatment of hypertension, avoiding the high initial micturition peak that usually occurs with furosemide dosage forms on the market.

Sustained-release formulations are intended to provide a longer duration of pharmacological response after administration of dosage forms than that which regularly occurs after administration of immediate-release dosage forms. The purpose of these preparations is

ensure a constant concentration of the active substance in body fluids over a certain period of time. However, the demand for dosage forms with controlled release is huge, the maximum therapeutic effect should be achieved using the minimum amount of active substance, in order to reduce the frequency and degree of side effects, as well as the differences in the external and internal individual effect.

Controlled release particles are preferably based on the use of polymer membranes that adjust and control the release of the active substance. In general, the polymer membrane consists of a film-forming agent and additives such as hydrophilic polymers, plasticizers, and pigments, and the release of the active substance occurs according to different release profiles, for example, pH-dependent, pH-independent, with no lag time.

One important type of controlled-release polymer membranes are membranes that provide pH-independent release of the active substance in the pH range of 1-8. At this pH range, the agent that creates the film is insoluble, so the release of the active substance occurs as a result of diffusion through the polymer membrane. The release rate is therefore primarily covered by the solubility and distribution of the active substance in the polymer membrane, the thickness of the polymer membrane and the porosity of the polymer membrane.

The invention provides a solution to the above-mentioned problem in that it relates to a controlled-release preparation comprising controlled-release particles containing furosemide, providing a significant reduction in blood pressure while the micturition caused by the composition is minimized, and resembles the natural micturition observed in patients. The invention therefore provides the possibility of balancing the desired pharmacological response, that is, the reduction of blood pressure in humans caused by furosemide, with the negative side effects such as a rapid urge to urinate.

Previous knowledge

US Patent 4,324,779 describes a method of treating hypertension with a low sustained release formulation of furosemide. Pellets containing furosemide, which are filled in gelatin capsules, basically consist of a furosemide core with a sustained-release coating that begins to dissolve in a weakly acidic environment.

US Patent 4,888,179 describes a multipart dosage composition comprising furosemide which is characterized by a special release rate at pH 1.5, 5.5 and 7.5. The composition consists of round granules coated with an inner layer consisting of ethyl cellulose and hydroxypropylmethyl cellulose and an outer layer consisting of hydroxypropyl methyl cellulose phthalate.

US Patent 4,983,401 describes a sustained release formulation using pH controlled diffusion through a membrane composed of a pH sensitive film forming polymer. The film forming polymer is hydrophobic in the pH range found in the stomach and hydrophilic in the pH range found in the intestine.

PCT/FI92/00242 describes a long-acting pharmaceutical composition comprising a core containing the active ingredient in a fast-release form and a coating containing the active ingredient in a slow-release form.

EP 475 536 describes a technique for coating cores with a dispersible powder containing the active drug and low substituted hydroxypropyl cellulose. The resulting granules show increased granule strength and improved disintegration properties.

US Patent 4,713,248 describes a multicomponent controlled release composition containing an active substance coated with a water-based film, comprising a homogeneous combination in water of a film-forming dispersing agent and a polymeric substance that enables the compaction of the coating.

US Patent 4,938,968 describes a controlled release formulation containing pellets of only one type of indomethacin. Pellets refer to indomethacin in an immediate and gradual release form.

Presentation of the invention

We have now surprisingly found that the problems mentioned above, that is, the non-uniform micturition cross-section involving a significant initial increase in micturition after administration of furosemide, have been solved with the new pharmaceutically controlled release particles of the present invention, using the minimum amount of furosemide required for maximum therapeutic effect. , thus keeping urination at a level that corresponds to the patient's usual urination cycle. Said controlled release particles comprise a core of insoluble soluble inert substance overlaid with furosemide dispersed in a hydrophilic polymer and coated with an outer membrane comprising a film forming agent selected from ethyl cellulose and a copolymer of acrylic and methacrylic acid esters and at least one hydrophilic polymer selected from polyvinylpyrrolidone , hydroxypropyl cellulose and polyalkylene glycol, where the amount of the outer membrane is between 35 and 65% (by weight) based on the dry superimposed core and a furosemide release cross-section of not more than 30% after 60 minutes, not more than 44% after 120 minutes and not more of 80% after 360 minutes.

As already mentioned above, the film forming agent is selected from ethyl cellulose and acrylic and methacrylic acid ester copolymers (for example Eudragit®RL, Eudragit®RS). In the case of using different qualities of acrylic resins as a film-forming agent, the permeability of the polymer membrane enables the selection of different qualities of acrylic resins, such as Eudragit®RL, Eudragit®RS, by varying the amount and combination of acrylic resins. Organic solutions and aqueous dispersions of film forming agents, as will be appreciated by one skilled in the art, can be used to form membranes. The preferred film-forming agent is ethyl cellulose.

The hydrophilic polymer incorporated into the polymer membrane, in order to adjust the permeability of the polymer membrane, is selected from polyvinylpyrrolidone, polyalkylene glycol and hydroxypropyl cellulose, of which hydroxypropyl cellulose is the most preferred. A preferred polyalkylene glycol is polyethylene glycol.

The amount of hydrophilic polymer in the outer membrane is between 20 and 50% (by weight). A preferred amount of hydrophilic polymer in the outer membrane is between 30 and 45% (by weight), a more preferred amount of hydrophilic polymer in the outer membrane is between 35 and 45% (by weight). The most preferred amount of hydrophilic polymer in the outer membrane is between 32 and 39% (by weight), especially between 35 and 39% (by weight).

The preferred amount of hydrophilic polymer in the outer membrane is 35-45% (by weight) and most preferably 35-39% (by weight) if the hydrophilic polymer is hydroxypropyl cellulose, 25-35% (by weight) if the hydrophilic polymer is a combination of hydroxypropyl cellulose and polyvinylpyrrolidone and 35- 45% (by weight) if the hydrophilic polymer is polyethylene glycol.

A combination of a film-forming agent, ethyl cellulose, and a hydrophilic polymer, hydroxypropyl cellulose, as the outer membrane has been found to be desirable for obtaining the desired release cross-section of furosemide from controlled release particles.

Coating the dry furosemide coated cores with a 35-65% (w/w) polymer (outer) membrane has been found to be necessary to enable a desirable release cross section and therefore a desirable voiding cross section and also to enable compression of the particles into tablet formulations, also including pharmaceutically acceptable excipients, their filling hard gelatin capsules. The preferred amount used is 45-55% (by weight) to obtain the desired release cross section of furosemide from the controlled release particles.

The hydrophilic polymer in which furosemide is dispersed is common, such as polyvinylpyrrolidone, polyalkylene glycol, gelatin, polyvinyl alcohol, starch and its derivatives, and cellulose derivatives.

An insoluble or soluble inert substance from which the cores are made is also common and can be sugar balls or sand particles (silica). An inert substance is a non-pharmacologically active substance. The size of the core particles is preferably around 0.1-0.3 mm.

Preferred controlled release particles comprise a sandy core coated with furosemide dispersed in polyvinylpyrrolidone and coated with an outer membrane comprising 55-65% (by weight) ethylcellulose and 35-45% (by weight) hydroxypropylcellulose.

Another preferred type of controlled release particles comprises a sandy core coated with furosemide dispersed in povinylpyrrolidone and coated with an outer membrane comprising 55-65% (wt) ethylcellulose and 35-45% (wt) polyethylene glycol.

Another preferred type of controlled release particles comprises a sandy core coated with furosemide dispersed in polyvinylpyrrolidone and coated with an outer membrane comprising 65-75% (by weight) ethylcellulose and 25-35% (by weight) a combination of polyvinylpyrrolidone and hydroxypropyl cellulose.

Given the limited solubility of furosemide at gastrointestinal pH 1-8, the release cross-section obtained using a controlled-release polymer membrane consisting only of a film-forming agent is completely inadequate for obtaining clinically significant results. However, it was found that by incorporating a hydrophilic polymer with the film-forming agent, greater permeability of the polymer membrane is enabled. Therefore, the release profile of furosemide from a controlled release formulation can be monitored, controlled and adjusted to produce pharmacologically desired results in patients. This means that the release profile of furosemide from controlled release particles according to the invention is primarily covered by the choice of ratio of hydrophilic polymer to film forming agent and the total amount of film forming agent and hydrophilic polymer applied to the furosemide overlaid core.

The invention also provides a novel controlled release composition containing furosemide with clinical and pharmaceutical advantages, therefore providing a pharmaceutical composition for the treatment of cardiovascular diseases, such as mild to moderate hypertension, congestive heart attack and edema, with limited unwanted side effects, such as is a quick burst of urination. The controlled-release composition of furosemide comprises the particles according to the invention, described above, optionally together with pharmaceutically acceptable additives. The preparation is in the form of tablets or capsules. Pharmaceutical properties allow controlled-release particles to be converted into controlled-release tablets, keeping the furosemide release cross-section after compression of the controlled-release particles, so no changes in bioavailability and clinical effect occur. Therefore, the preparation according to the invention in the form of tablets or capsules has the same release cross section as the particles according to the invention.

The pharmaceutical preparation provided according to the invention is characterized by the special composition of the controlled-release membranes, the total amount of applied components of the controlled-release membrane on the furosemide-coated core, the cross-section of furosemide release from the controlled-release particles and the resulting urination cross-section.

The invention described above provides a controlled release of furosemide at a rate determined by a special USP XXIII method for the release of the active substance in vitro. The determination was carried out at pH 6.8 and a rotation speed of 100 revolutions per minute. The release of furosemide from the particles and from the preparation including said particles, provided by the invention, is not higher than 30%, preferably about 3-30%, after 60 minutes, not more than 44%, preferably 10-44%, after 120 minutes and more of 80% after 360 minutes.

One particular object of the invention is to provide a composition which provides an average micturition cross section and a low total micturition, when compared to commercially available furosemide compositions. The urination section, after administration of a single dose containing 60 mg of furosemide from the invention, was characterized in clinical observation with low and prolonged urination without significant changes in urination. Comparing the micturition cross section produced with the invention to the micturition cross section data obtained with available corresponding furosemide containing preparations supports these findings.

Pharmaceutical preparations

The above formulation, which includes controlled-release particles with release-controlling membranes, can be prepared by conventional methods such as surface spray fluid bed or Wurster or powder coating techniques, any technique well known to one skilled in the art. Insoluble or soluble inert core particles, such as sand particles, are coated with a dispersion containing furosemide and a hydrophilic polymer, using a conventional surface spray fluidized bed technique. The resulting furosemide-coated cores are then coated with a polymer membrane, which includes a film-forming agent and a hydrophilic polymer, using the Wurster liquid layer technique. Plasticizers can be added to the polymer membrane in order to improve the technical properties of the membrane and change the release properties. Examples of plasticizers that can be used are:

citrate esters, acetylated monoglycerides, and glycerin triacetate or any other plasticizer useful in preparing the film, as will be apparent to one skilled in the art.

When the controlled release particles are compressed into tablets, they are mixed with pharmaceutically acceptable additives to provide favorable filling, binding, lubricating and disintegrating properties. Examples of additives are microcrystalline cellulose, lactose, spray-dried lactose, dicalcium phosphate, pregelatinized starch, starches and their derivatives, such as sodium starch glycolate and maltodextrin, sorbitol, maltitol, cellulose and its derivatives, polyethylene glycol, polyvinyl pyrrolidone, caster sugar, stearic acid, magnesium stearate, sodium stearyl fumarate, molasses, colloidal silica, or any other common excipients useful in the preparation of the tablet, as will be apparent to one skilled in the art.

Additives contained in the tablet, together with particles with controlled release, can be used as direct additives for compression, they can be granulated into granules with favorable compression and flow properties. Disintegrants may or may not be added. Lubricants will normally be added. The amount of supplements, optional cereal grains, can range from 25 to 75% (by weight) of the total weight of the tablet. In order to obtain even more favorable compression properties, the proportions of additives should be between 40 and 75% (by weight) of the total weight of the tablet.

The amount of furosemide in the pharmaceutical preparations according to the invention is in the range of 10-100 mg, preferably in the range of 30-70 mg, more preferably in the range of 40-60 mg, the most preferred preparations have an amount of furosemide of 60 mg and 30 mg.

The following examples will illustrate, but not limit, the invention.

Examples

Superimposed cores:

Silicon dioxide (0.1-0.3 mm) 800 g

Water, purified 1500 g

Furosemide (90%<10 μm) 800 g

Polyvinyl pyrrolidone, K-30 400 g

Furosemide, dispersed in a solution of polyvinyl pyrrolidone (K-30) in water, is dispersed in sand (silicon dioxide) in the liquid bed granulator.

Coating solutions:

Example 1

Ethyl cellulose 260 g

Hydroxypropyl cellulose 140 g

Ethanol 3500 g

Example 2

Ethyl cellulose 258 g

Hydroxypropyl cellulose 142 g

Ethanol 3500 g

Example 3

Ethyl cellulose 256 g

Hydroxypropyl cellulose 144 g

Ethanol 3500 g

Example 4

Ethyl cellulose 252 g

Hydroxypropyl cellulose 148 g

Ethanol 3500 g

Example 5

Ethyl cellulose 248 g

Hydroxypropyl cellulose 152 g

Ethanol 3500 g

Example 6

Ethyl cellulose 240 g

Polyethylene glycol 160 g

Ethanol 3500 g

Example 7

Ethyl cellulose 280 g

Hydroxypropyl cellulose 60 g

Polyvinylpyrrolidone 60 g

Ethanol 3500 g

800 g of the dry resulting layered cores, as described above, were coated with ethyl cellulose and hydroxypropyl cellulose, by spraying with a solution of the mentioned substances in ethanol.

Composition for one tablet containing 60 mg of furosemide

Coated particles (Examples 1-7) 225.0 g

Microcrystalline cellulose (Avicel®PH 200) 337.5 g

Sodium starch glycolate 22.5 g

Magnesium stearate 0.06 g

The controlled release particles described in Examples 1-7 were mixed with microcrystalline cellulose, and further mixed with sodium starch glycolate. Magnesium stearate was admixed and the mixtures were compressed into tablets in a single tablet press at a compression force of 10 kN (±1 kN) at a compression speed not exceeding 70 tablets per minute. Flat holes with a diameter of 11 mm were used. Tablets disintegrate within 30 seconds in 1000 mL of purified water at 37°C releasing particles with controlled release.

The in vitro release, according to the USP XXIII Paddle Method, of 1000 mL buffered solution at pH 6.8, tablets pressed at 10 kN, containing 60 mg of furosemide, is shown in Table 1.

Table 1

Percentage of furosemide released from controlled-release tablets, according to the USP XXIII paddle method, at pH6.8 (n=3)

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Conclusion

The invention described herein provides a reproducible and controllable release rate of the active ingredient, furosemide, by applying a specific amount of a special controlled release membrane comprising a film forming agent and a hydrophilic polymer. The invention described herein has advantageous properties for the treatment of hypertension by providing a total micturition after oral administration similar to the normal level of micturition observed in patients, thereby maintaining a controlled-release composition containing furosemide suitable for long-term treatment of hypertension.

The urine sections, shown in Figure 1, were taken from a controlled clinical trial in 12 healthy human subjects, comparing the preparation according to the invention and the reference product of furosemide with delayed release available on the Swedish market, named Lasix®, Retard® storage capsules containing furosemide according to SWEDIS , sucrose, stearic acid, ethanol, ethyl acetate, Shellac, polyvidonum, aluminum hydroxide gel and corn starch. It has been clearly demonstrated that the preparation according to the invention has significant and favorable properties with regard to urination. A micturition similar to the normal micturition observed in patients, that is, a micturition cross-section, as an achievement of the invention, provides a normal micturition cross-section over a period of time and the clinically undesirable initial high micturition peak is removed with the present invention, thereby retaining the fundamental advantages of a controlled-release dosage form for long-term treatment with furosemide for conditions such as high blood pressure.

Claims (27)

1. Controlled release particles, comprising an insoluble or soluble inert substance, which is superimposed with furosemide dispersed in a hydrophilic polytner and coated with an outer membrane, characterized in that said outer membrane includes 1) a film-forming agent selected from ethyl cellulose and acrylic and methacrylic acid ester copolymers and 2) at least one hydrophilic polymer selected from polyvinylpyrrolidone, hydroxypropyl cellulose and polyalkylene glycol; and the amount of the outer membrane is between 35 and 65% (by weight) based on the dry overlaid core; and that the release cross-section of furosemide is not higher than 30% after 60 minutes, not higher than 44% after 120 minutes and higher than 80% after 360 minutes. 2. Particles with controlled release according to claim 1, characterized by the fact that the non-lead agent for the formation of the film is ethyl cellulose. 3. Controlled release particles according to any of claims 1-2, characterized in that the hydrophilic membrane polymer is hydroxypropyl cellulose. 4. Controlled release particles according to any one of claims 1-3, characterized in that the hydrophilic polymer of the membrane is polyethylene glycol. 5. Controlled release particles according to any one of claims 1-4, characterized in that the hydrophilic polymer of the membrane is a combination of hydroxypropyl cellulose and polyvinylpyrrolidone. 6. Controlled release particles according to any one of claims 1-5, characterized in that the amount of hydrophilic polymer in the outer membrane is between 20 and 50% (by weight). 7. Controlled release particles according to any one of claims 1-6, characterized in that the amount of hydrophilic polymer in the outer membrane is between 30 and 45% (by weight). 8. Controlled release particles according to any one of claims 1-7, characterized in that the amount of hydrophilic polymer in the outer membrane is between 35 and 45% (by weight). 9. Controlled release particles according to any one of claims 1-8, characterized in that the amount of hydrophilic polymer in the outer membrane is between 32 and 39% (by weight). 10. Controlled release particles according to any one of claims 1-9, characterized in that the amount of hydrophilic polymer in the outer membrane is between 35 and 39% (by weight). 11. Controlled release particles according to any one of claims 1-6, characterized in that the amount of hydrophilic polymer in the outer membrane is 35-39% (by weight) if the hydrophilic polymer is hydroxypropyl cellulose, 25-35% (by weight) if it is hydrophilic polymer combination of hydroxypropyl cellulose and polyvinylpyrrolidone and 35-45% (by weight) if the hydrophilic polymer is polyethylene glycol. 12. Controlled release particles according to any one of claims 1-11, characterized in that the core is made of sand (silica). 13. Controlled release particles according to any one of claims 1-12, characterized in that they comprise a sandy core overlaid with furosemide dispersed in polyvinylpyrrolidone and coated with an outer membrane comprising 55-65% (by weight) ethyl cellulose and 35-45% ( by weight) of hydroxypropyl cellulose. 14. Controlled release particles according to any one of claims 1-12, characterized in that they comprise a sandy core overlaid with furosemide dispersed in polyvinylpyrrolidone and coated with an outer membrane comprising 55-65% (by weight) ethyl cellulose and 35-45% ( by weight) of polyethylene glycol. 15. Controlled release particles according to any one of claims 1-12, characterized in that they comprise a sandy core overlaid with furosemide dispersed in polyvinylpyrrochdone and coated with an outer membrane comprising 65-75% (by weight) ethyl cellulose and 25-35% ( by weight) of combinations of polyvinylpyrrolidone and hydroxypropyl cellulose. 16. Method for the preparation of particles with controlled release according to any one of claims 1-15, characterized in that furosemide is dispersed in a hydrophilic polymer solution, dispersed on insoluble or soluble inert cores, giving a layer of furosemide and then the outer membrane is dispersed over the layer of furosemide. 17. Pharmaceutical preparation, comprising particles with controlled release, according to any one of claims 1-15, characterized in that it is optionally combined with pharmaceutically acceptable additives. 18. Pharmaceutical preparation according to claim 17, characterized in that the amount of furosemide is in the range 10-100 mg. 19. Pharmaceutical preparation according to claim 18, characterized in that the amount of furosemide is in the range 30-70 mg. 20. Pharmaceutical preparation according to claim 19, characterized in that the amount of furosemide is in the range 40 - 60 mg. 21. Pharmaceutical preparation according to claim 20, characterized in that the amount of furosemide is 60 mg. 22. Pharmaceutical preparation according to claim 20, characterized in that the amount of furosemide is 30 mg. 23. Pharmaceutical preparation according to any one of claims 17-22, characterized in that it is in the form of tablets. 24. Pharmaceutical preparation according to any one of claims 17-22, characterized in that it is in the form of capsules. 25. The method of manufacturing a pharmaceutical preparation according to any one of claims 17-23, characterized in that the particles are pressed into tablets by mixing pharmaceutically acceptable additives. 26. Controlled release particles according to any one of claims 1-15, characterized in that they are used for the production of a drug for the treatment of cardiovascular diseases, such as hypertension, congestive heart attack and edema. 27. A method of treating hypertension, edema and congestive heart attack, characterized in that the pharmaceutical preparation according to any one of claims 17-24 is administered to a host in need of such treatment.