DK175608B1 - New dosage form - Google Patents

Description

in DK 175608 B1

Description

The present invention relates to a controlled release oral pharmaceutical polydepot dosage form wherein individual units containing an active substance are surrounded by a coating which dispenses the active substance by diffusion.

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Technical background

The term "controlled release polydepot formulation" (Bechgaard & Heger-mann Nielsen, 1978) refers to a pharmaceutical formulation comprising a plurality (typically at least 100) of individually coated (or "microencapsulated") units contained in the formulation in such form, that the individual units will be made available from the formulation after digestion of the formulation in the stomach of animals, including humans who have taken the formulation. Typically, the polydepot formulation may be a gelatin capsule or tablet which breaks down in the stomach, making a plurality of coated units available.

Controlled release polydepot formulations aim for a controlled release of active substance in a predetermined pattern to reduce and delay the maximum plasma concentration without affecting the extent of drug availability. Due to the lower maximum plasma concentration, the frequency of undesirable side effects may be reduced, and due to the delay in the time taken to reach the maximum plasma concentration and the extension of time over the therapeutically active plasma concentration, the dosing frequency may be reduced to a dose intake of only two or once per day to improve patient compliance.

A further advantage of the controlled release polydepot dosage form is that a high local concentration of the active substance in the gastrointestinal system is avoided because the depots are distributed freely throughout the gastrointestinal tract.

Drug delivery from a controlled release dosage form is usually controlled by a coating on the outside of an active core. The release can be obtained a)! by diffusion: coated swells in aqueous environment so that the active substance can 30

I DK 175608 B1 I

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You diffuse through the stagnant liquid phase contained in the coating

In the polymer, or b) by osmosis: the coating is semipermeable, i.e. water only

You can penetrate the coating polymer and dissolve the active substance; which will lead you

In for a build-up of pressure within the coating; to allow the active substance to remain

In 5 released from the unit, a hole or channel having a well-defined area must be formed in I

In the coating, this can be achieved either by laser drilling {SE Patent 435,897 - US I

In Patent 4256108 by Alza) or by incorporating a substance which after ingestion you will

In forming the channels by erosion (US Patent 4687,660 and EP Patent Application 0171 I

In 457 by Wellcome), if the coating has any weak points or cracks, you will

In this, the release area increases and results in varying release rates for I

In different units, ie. zero order delivery will not be achieved for the entire dose

In the ring, or c) by erosion: the coating will disintegrate by a process that is I

Depending on, for example, enzymes or pH, leaving the active core exposed to fast I

In solution. The importance of a pH-independent diffusion in obtaining an I

In reproducible accessibility rate and to minimize intra- and interindividuals

Dual variations are known (GB Patent No. 1,468,172 and Bechgaard & Baggesen, I

In 1980). It is also known that regulated drug delivery in vivo can be achieved by I

In an erosion process by entero-coating of a polydepot dosage form I

I (Green, 1966; McDonald et al., 1977; Bogentoft et al., 1978). IN

I 20 I

The present invention relates to polydepot dosage forms controlled by I

With the help of diffusion membranes. Unlike the known diffusion mem- I

In branes used for polydepot dosages, the membranes of I are swollen

In the invention not in water and gastrointestinal fluids. Furthermore, the used I

In 25 polymer be insoluble in and impervious to water and after ingestion I

In the membrane, pores are formed by a pH-independent erosion process. The pores you will

You give the coating a mushroom-like appearance and will be filled with stylus

In the end fluid where the active substance can diffuse from the core. IN

Description of the Invention

It has been observed that a number of coatings used in connection with I

In controlled release pharmaceutical polydepot formulations, it has the drawback, I

In that their delivery characteristics change over time. This means it is not you

It is possible to maintain a reproducible release rate for an active substance contained in the polydepot formulation, since a variable release rate has been observed for such coatings. In accordance with the present invention, it has surprisingly been found that by selecting a particular type of controlled release system which has not been previously used or described for polydepot formulations, many problems associated with polydepot formulations can be avoided.

On a macro scale, ie For tablets, controlled release systems based on 10 coatings containing pore-forming substances have been disclosed, for example, in GB Patent No. 1,186,990, U.S. Patent No. 3,538,214, and in U.S. Patent No. 4,557,925. The present delivery system is based on the principle that a core comprising an active substance is coated with a film consisting essentially of a polymer which is insoluble in and impermeable to water and gastrointestinal fluids, and wherein a water-soluble pore forming substance is randomly distributed. It is also necessary that the polymer cannot be swollen in water and gastrointestinal fluids. By using this controlled release system for polydepot formulations, it was surprisingly found that important benefits could be obtained.

Thus, it has been found that it is possible to coat different particle types, including crystals, in ordinary coating equipment, i.e. in various types of standard equipment normally available in the pharmaceutical industry.

It follows that the manufacturing process is relatively simple and inexpensive. Furthermore, it has been found that a uniform, substantially zero-order, controlled release rate could also be obtained when relatively non-uniform particles were used as cores. This is usually not the case for conventional controlled release polydepot formulations. For example, diffusion controlled release from polydeposits where the polymer swells is dependent on the thickness of the diffusion layer which will change over time as the polymer will release the active substance as the swelling continues. This will lead to different release rates at the beginning and end of the delivery period, which will result in a release that is more similar to first order release than zero order. On the other hand, osmotically regulated polydeposits are both dependent on the ability of the substance in the core to draw water into it, which may result in decreased release rate at the end of the release period if the osmotic active substance and the drug substance are not -

I DK 175608 B1 I

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The same, and the quality of the coating, as in the case of weak points or

In cracks therein the release area increases. Such errors cause varying triggers

Input speeds for different devices, i. that you do not want to give zero order

You are obtained for the variety of units contained in a dose. IN

I 5 I

Another advantage of the present invention is the ability to adapt I

In the rate of release by changing the film thickness. In the polydepot systems that I

Currently used commercially, this possibility seems to exist on a theme

In a very unpredictable way and only up to a certain film thickness. In contrast, I

In 10, in the present system, there exists a substantially linear correlation I

In between the release rate and the film thickness. This means that for a given I

In film type, the rate of release decreases proportionally with the increase of I

In the film thickness in accordance with Fick's first law of diffusion. IN

I 15 It is also possible to change the rate of delivery by changing the ratio of I

In the pore-forming substance and coating polymer. This gives the present I

In system a unique opportunity to utilize active substances with great advantage

In different solubilities, which is a great advantage over the existing I

In controlled release polydepot systems. IN

I 20 I

Thus, in one aspect of the invention, an oral pharmaceutical polydepot formulation I relates

With controlled delivery, which formulation is characterized by individual I

In units contain an active substance and the units are provided with an outer I

In a coating consisting essentially of a polymer which is insoluble in, for one week

In 25 easy to swell and non-swellable in water and gastrointestinal fluids, and a water solution.

In soluble pore forming substance which is randomly distributed in the polymer. Another aspect I

I of the invention relates to a formulation in which the units of the above described I

In type are combined with non-coated units comprising the same I

Or other active substance for immediate release thereof, and / or with non-diffusion

In 30 sion coated units which have been provided with a coating selected from I

In hydrophilic coatings, hydrophobic coatings, water based coatings and organic I

In coatings, which impart desired properties to the units such as resistance over I

For acid or base, storage stability, taste masking, light stability,

In color, improved processing ability, etc. The relationship between diffusion coatings and I

In non-coated or non-diffusion coated units in the composition, you can

For example, it is adapted to the desired release characteristics of the composition, but it is preferably in the range of from approx. 10:90 to 90:10 of diffusion-coated devices ten! uncoated or non-diffusion coated devices.

The controlled release oral pharmaceutical polydepot formulation of the invention will typically be a gelatin capsule containing a plurality of the units, typically more than 100, a portion pack containing a plurality of the units, typically more than 500, or a tablet made from a plurality of the units, typically more than 100, in such a way that the loss of ingestion will fall into the stomach into a plurality of individual units. In each of the three formulations listed above, the units shortly after ingestion will be freely distributed throughout the gastrointestinal tract. .

Detailed Description of the Invention 15 Coatings

The coating polymer should have good film-forming and adhesive properties and should be readily soluble in organic solvents such as acetone, methylene chloride, methyl ethyl ketone or mixtures of acetone and ethanol or methylene chloride. Suitable polymers are non-swelling cellulose derivatives, acrylic polymers and vinyl polymers. The coating polymer is a polymer containing 80-95% by weight vinyl chloride, 1-19% by weight vinyl acetate and 0-10% by weight vinyl alcohol. Preferably, it contains 88-94 wt% vinyl chloride, 2-5 wt% vinyl acetate and 3-5 wt% vinyl alcohol.

It is preferred that plasticizers are also present in the coating. The amount may vary between 1-50% by weight based on the coating polymer, preferably between 10-40% by weight. Examples of suitable plasticizers are acetyl tributyl citrate, polyethylene glycol, blown castor oil and glyceryl triacetate. Furthermore, the coating may comprise sodium hydrogen carbonate as a stabilizer in amounts between 1 and 20% by weight based on the coating polymer, preferably 5-15% by weight, based on the coating polymer.

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DK 175608 B1 I

The pore forming substance used according to the present invention should have I

high solubility in water, being insoluble in the solvent used for I

coating, pharmacologically acceptable and substantially free of proprietary pharmaco-I

logical effects in the quantities used. In particular, sugars such as H are preferred

5 sucrose and lactose and salts such as sodium chloride. IN

The particle size of the pore-forming substance can vary between 0.1 µπη and 100 µm, I

preferably between 0.5 µm and 50 µm. The ratio of the amount of the pore-I

The coating material and coating polymer depend on the desired release rate. H

Generally, the ratio should be between 0.05 µm and 5 µm, preferably between H

0.1 pm and 2 pm. H

The thickness of the coating also depends on the desired release rate. H

It may vary between 5 µm and 300 µm, preferably between 10 µm and 150 µm. H

The individual units of the polydepot formulations of the invention are above-H

drawn cores consisting of crystals or pellets. The crystal units are in it

significant monolite crystals. Pellets are a combination of active substance and I

excipients. One main type of pellets consists of a graft particle of excipient I

20 with active substance disposed on the surface thereof. Typical pellets of this type are the fl

so-called "non-pareil" pellets, where the inoculants are in the form of spherical I

saccharosepartikler. In another pellet formulation principle of this type, graft H is

the substances present in the form of crystalline sucrose. IN

Another major type of pellet consists of particles having a substantially homo-

gene cross section prepared, for example, by wet granulation or extrusion. IN

The diameter of the cores is usually approx. 0.1-1.5 mm, preferably approx. 0.4-1.2 mm, especially I

with an area of approx. 0.4 mm in a specific formulation. IN

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The active substance in the formulations of the invention may be any

active substance which can be advantageously administered in polydepot formulations with re-I

yellowed discharge. Examples of suitable active substances are found in almost all of them

therapeutic groups comprising diuretics, antiepileptics, sedatives, anti-I

35 arrhythmics, antirheumatic agents, β-blockers, vasodilators, analgesics, I

I DK 175608 B1 I 7 In bronchodilators, hormones, vitamins, oral antidiabetics, antibiotics, anti-hypertensives, anti-inflammatory drugs, antimicrobials and antidepressants, polypeptides, enzymes and mucopolysaccharides.

I Examples of active substances include phenylpropanolamine, potassium chloride, I quinidine salts, lithium carbonate, acetylcysteine, depyridamole, theophylline, cholintheo-Iphyllinate, dextropropoxyphene, dextromethorphan, salbutamol, terbutaline, digoxin, digoxin, digoxin, digoxin, morphine, nitroglycerin, I clonidine, disopyramide, verapamil, captopril, prazocin, nifedipine, diltiazem, para I cetamol, indomethacin, ticlopedin, oxybutynin and noscapine.

Among these substances, some are characterized by having a pH-independent solubility, others by having a pH-dependent solubility. Active substances having a pH-dependent solubility are preferably incorporated into cores in combination with buffer agents such as sodium bicarbonate, citric acid, succinic or tartaric acid to obtain a solution of active substance which is substantially independent of the pH variations in the gastrointestinal system that the units will pass through.

In Process I 20 In general, the process for preparing the coated polydepot composition of the invention will comprise the following steps: dissolving the polymer in a solvent, preparing a suspension of the pore-forming substance, mixing the suspension of the pore-forming substance and dissolving the polymer in the solvent. for forming a coating liquid, producing polydepot cores 25 containing an active substance in the form of crystals or pellets, using the core units to apply the coating liquid and drying the units to evaporate the solvent and provide polymer-coated polydeposits with the water-soluble, pre-pore-forming, pore-forming, pore-forming.

For example, the solvent of the polymer may be selected from acetone, methylene chloride, methyl ethyl ketone or mixtures of acetone and ethanol or methylene chloride.

The pore-forming particles are micronized either by dry grinding or by wet grinding to a predetermined particle size, preferably between 0.5 μίτι and 50 μη-ι. particles

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The Ies are dispersed in solvents such as those previously mentioned and mixed with I

In the terpolymer solution. IN

The coating liquid may, as previously stated, include a plasticizer and sodium I

In 5 hydrogen carbonate. IN

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In coloring agents can also be incorporated into the coating liquid, and there- fore

You draw insoluble coloring materials. IN

The suspension liquid in the form of a suspension is then applied to drug I

In drug-containing cores. A particularly advantageous step is that the coating process I

You can perform in ordinary coating equipment, ie. in different types of standard I

In equipment normally available in a pharmaceutical industry. This is due to over- I

In the good film-forming and adhesive properties of the drawing material and the lightweight I

In 15 solvent evaporation from the system. Examples of such coating I

In equipment, boiler coating is in sugar coating boilers or perforated films

In coating boilers, Wurster coating and other "fluid bed" coatings I

In procedure procedures. It follows that the manufacturing process is relatively easy and inexpensive. IN

The following non-limiting examples further illustrate the invention. IN

In Example 1 I

In Theophylline is a weak acid (pK8 = 8.7) which is slightly soluble in water. The cores I

In 25 used in this example, 60% contains theophylline on non-pareils and has an I

In particle size of 0.8-1.0 mm. These cores (1.0 kg) are coated with an I

In coating suspension having the following composition:

In Terpolymer containing 92% by weight of vinyl chloride I

In 4% by weight vinyl acetate and 4% by weight vinyl alcohol 390 g I

Micronized sucrose (particle size 1-10 µm) 930 g I

I Acetyltributyl citrate 89 g I

I Blown castor oil 68 g I

I Sodium Hydrogen Carbonate 34 g I

I 35 Acetone to 10,000 g I

DK 175608 B1 9

The coating suspension is applied to the cores by means of an airless syringe coating device in a coating boiler. Samples are taken after application of 1.0, 2.0 and 3.0 kg of the suspension.

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Table 1 shows the rate of release of a dose corresponding to 90 mg of theophylline. The trigger test is performed according to the USP XXI basket method (100 rpm). There is a linear correlation between the release rate and the thickness of the coating, and the release rate is essentially independent of pH. A uniform zero order delivery rate is observed for most of the delivery period.

Table 1 Time Amount of theophylline delivered (%)

(h) 0.2M TRIS buffer pH 7.4 0.1M HCl

ABC

I 46 18 10 11 20 2 84 39 24 28 3 98 58 37 44 4 100 76 49 59 5 90 62 73 6 96 73 86 25 7 99 83 94 8 90 99 9 94 100 10 96 101 II 97 101 30 12 98 102 A: '2.5 mg coating material per Core B: 5.9 mg coating material per cm2 cm 2 core 35 C: 9.0 mg coating material per cm2 core

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EXAMPLE 2 I

In Cholintheophylline is a salt of theophylline, which is easily soluble in water. The cores I

As used in this example, 30% contains choline theophyl linate on sugar crystals

In 5 and has a particle size of 0.7-1.0 mm. These cores (1.0 kg) are coated

I with a suspension having the following composition:

I Terpolymer containing 92% by weight of vinyl chloride I

In 4% by weight vinyl acetate and 4% by weight vinyl alcohol 295 g I

Micronized sucrose (particle size 1-10 µm) 930 g I

I Acetyltributyl citrate 30 g I

I Blown castor oil 23 g I

I Sodium Hydrogen Carbonate 34 g I

In Titanium Dioxide 59 g I

I 15 Acetone to 10,000 g I

In the coating suspension, the cores are applied with an airless syringe coating

Icing device in a coating boiler. Samples are taken after application of 2.0 I

In 2.5 and 3.0 kg of suspension. IN

I 20 I

Table 2 shows the rate of release of a dose equal to 90 mg of theophylline. IN

In the Trigger test according to the USP XXI basketball method (100 rpm). IN

The dissolution rate is significantly higher than in Example 1 because of the I

In much higher solubility of theophylline choline salt than of pure theophylline. On I

At 25, despite the higher triggering rate, there is still a linear correlation between the two

In the limb the rate of delivery and the thickness of the coating. IN

Η I

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DK 175608 B1 11

Table 2

Time Delivered amount of theophylline (%) (hours) 0 # 2M TRIS buffer pH 7.4 5

A B C

0.33 96 86 76 0.67 100 99 98 1.00 100 100 10 __ A: 3.7 mg coating material per Core B: 4.6 mg coating material per cm2 Core C: 5.5 mg coating material per cm2 cm2 core Example 3

Diltiazem hydrochloride is an ammonium salt which is easily soluble in water. The cores used in this example contain 44% diltiazem hydrochloride or non-20 pareils and have a particle size of 0.7-1.1 mm. These cores (0.9 kg) are coated with a coating suspension having the following composition:

Terpolymer containing 92% by weight vinyl chloride 4% by weight vinyl acetate and 4% by weight vinyl alcohol 409 g 25 Micronized sucrose (particle size 1-10 µm) 930 g

Acetyltributyl citrate 70 g. Blown castor oil 52 g

Sodium bicarbonate 34 g of Acetone to 10,000 g of 30

The coating suspension is applied to the cores with an airless syringe coating device in a coating boiler. Samples are taken after application of 1.6, 2.3 and 3.0 kg of the suspension.

I DK 175608 B1 I

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Table 3 shows the rate of dissolution of a dose equivalent to 120 mg of diltiazem-I

In hydrochloride. Examination of the trigger is performed according to USP XXI Basketball I

At the tip (100 rpm). The solubility of this ammonium salt is that of I

Therefore, the same as that of the salt of Example 2. The release rate is also I

In 5 the same. Here, too, there is an obvious, linear correlation between the output I

In the sizing speed and thickness of the coating. IN

In Table 3 I

For 10 Time Amount of diltiazem hydrochloride delivered (%) I

In (hours) 0.05M phosphate buffer pH 7.4 I

In ABC I

I 0.25 48 34 27 I

I 15 0.50 79 67 56 I

I 0.75 91 85 80 I

I 1.00 96 91 85 I

I 1.25 98 94 91 I

I 1.50 99 97 94 I

I 20 1.75 100 98 96 I

I 2.0 101 99 97 I

In A: 6.8 mg coating material per cm2 Core B: 9.8 mg coating material per cm2 core

25 C: 12.4 mg coating material per cm2 core I

Claims (8)

An oral pharmaceutical polydepot formulation comprising individual cores containing a pharmacologically active substance, said cores being provided with a coating consisting essentially of a polymer which is insoluble in, impermeable to and non-swellable in water and gastrointestinal fluids, wherein the coating polymer is a polymer containing 80-95% by weight vinyl chloride, 1-19% by weight vinyl acetate and 0-10% by weight vinyl alcohol, and a water-soluble pore-forming substance which is randomly distributed in the polymer, whereby the coated cores form H units which provides a substantially zero-order, diffusion-controlled, release rate of the active substances. IN A formulation according to claim 1, characterized in that the polymer is a terpolymer I containing 88-94% by weight vinyl chloride, 2-5% by weight vinyl acetate and I 3-5% by weight vinyl alcohol. IN Formulation according to any one of claims 1-2, characterized in that the pore-forming substance is selected from the group consisting of sugars and salts. IN Formulation according to any one of the preceding claims, characterized in that it also comprises uncoated cores containing the same or another active substance for immediate release thereof. IN A formulation according to any one of claims 1-4, characterized in that it also comprises non-diffusion-coated cores provided with a coating I selected from hydrophilic, hydrophobic, water-based and organic coatings. IN A process for preparing an oral pharmaceutical polydepot formulation comprising individual cores containing a pharmacologically active substance, which cores are provided with a coating consisting essentially of a polymer which is insoluble in, impermeable to and non-swellable in water. and gastrointestinal fluids, wherein the coating polymer is a polymer containing 80-95% by weight in vinyl chloride, 1-19% by weight vinyl acetate and 0-10% by weight vinyl alcohol, and in a water-soluble pore-forming substance randomly distributed in the polymer, wherein coated cores form units that provide a substantially zero. In the order of diffusion controlled release rate of the active substance which comprises the following steps: dissolving the polymer in a solvent, preparing a suspension of the pore forming substance, mixing the suspension of pore forming substance and dissolving the polymer in solvent I to form a coating liquid, preparing polydepot nuclei containing et an active substance in the form of crystals or pellets, applying the coating liquid to the core units, and drying the units to evaporate the solvent and providing the polymer. polyunits with the water-soluble pore-forming substance randomly distributed within the coating. Process according to claim 6, characterized in that the polymer is a terpolymer containing 88-94% by weight vinyl chloride, 2-5% by weight vinyl acetate and 3-5% by weight vinyl alcohol. 4 Process according to any one of claims 8-10, characterized in that the pore forming substance is selected from the group consisting of sugars and 10 salts. Λ,