CH623232A5 - Device for delayed pharmaceutical release and process for its production - Google Patents

Description

The invention is illustrated by the following examples. Unless otherwise stated, parts and percentages are always parts by weight and percentages by weight.

example 1

A. Preparation of a mixture of drug, polymer and soluble substance

Hydrocortisone (trade name cortisol), ethylene-vinyl acetate copolymer (40% vinyl acetate, melt index approximately 45 to 70, trade name Elvax 40) and sodium chloride (number average diameter 40 μm) were mixed on a mill in the proportions given below .

Quantitative ratio

Mixture of hydrocortisone polymer NaCl

No. (%) {%) (%)

l (a) 10 90 0

l (b) 10 87.5 2.5

l (c) 10 85 5

These mixtures were then passed through the chilled rolls of a small mill to form raw 0.75 mm thick sheets. The sheets were pressed in a hydraulic press at 57 ° C for 5 minutes to 0.4 mm thick films.

B. Production and testing of eye inserts

Several identical elliptical eye inserts (13.5 x 5.8 x 0.4 mm) were punched out from the foils according to Part A. Each eye insert contained approximately 2 mg hydrocortisone. These inserts were placed in a mock aqueous eye fluid and the amount of hydrocortisone released was determined at various time intervals using a UV spectrometer at 248 nm (nanometers). Delivery rates in «g / h. calculated. These delivery rates are plotted in Fig. 1.

The eye inserts made from Mixtures 1 (b) and 1 (c) had their effective surface area increased within the first 5 hours of the study by the water-blasting mechanism described above. After this time, the NaCl release from the inserts was less than 100 / zg / hour. like.

Example 2

A. Preparation of mixtures of drug, polymer and soluble substance.

As in Example 1, mixtures of hydrocortisone, ethylene-vinyl acetate copolymer and sodium chloride were prepared in the proportions given below. These mixtures were processed into films as in Example 1.

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Quantitative ratio

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623 232

Quantitative ratio

Mixture of hydrocortisone polymer NaCl Mixture of idoxuridine polymer NaCl

No. (%) {%) (%) No. (%) (%) (%)

2 (a) 30 70 0 3 (a) 65 35 0

2 (b) 30 68.75 1.25 3 (b) 65 34.5 0.5

2 (e) 30 67.5 2.5 3 (c) 65 34 1.0

2 (d) 30 65 5 3 (d) 65 33 2.0

2 (e) 30 60 10 10 3 (e) 65 31 4.0

2 (f) 30 55 15 3 (f) 65 29 6.0

B. Production and Testing of Eye Inserts Several identical inserts from the films according to Part A were produced and tested as in Example 1. The delivery speeds of these inserts are plotted in FIG. 2. Like the inserts of Fig. 1, these inserts also increased their effective surface area within approximately the first 5 hours of the study.

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Example 3

A. Preparation of Mixtures of Drug, Polymer and Soluble Idoxuridine (number average diameter about 15 µm), the copolymer of Example 1 and sodium chloride (number average diameter 40 / xm) were carried out using the procedure of Example 1 in the below specified proportions mixed. The mixtures were processed to 0.3 mm thick films using the procedure of Example 1.

B. Production and testing of eye inserts

Four identical elliptical eye inserts (13.5 x 5.8 x 0.3 mm), each weighing about 22 mg, were made and tested using the general procedure of Example 1. The delivery of idoxuridine was monitored at 288 nm. The delivery speeds of these devices are plotted in FIG. 3. Like the inserts of Fig. 1, these inserts increased their effective surface area within about the first 5 hours of the study.

The effects of adding small amounts of sodium chloride to the inserts of Examples 1 to 3 are evident from Figures 1 to 3. The rate of release of the drug from the sodium chloride-containing inserts is significantly greater than the release rate of drugs from inserts that do not contain sodium chloride. The release time is significantly reduced with higher sodium chloride contents.

s

2 sheets of drawings

Claims (4)

623 232 1. A device for delayed drug delivery, which a) is used in an aqueous environment of the human or animal body and thereby releases the drug essentially by diffusion, b) has an integral, solid structure of such a shape and size that it is integrated into the Environment in which it is to be used can be introduced and held there, and c) consists of a mixture which is a nonionic drug with a water solubility of 200 to 10,000 ppm and a permeable to the drug and in the aqueous environment at least during the duration of the drug delivery insoluble polymer, characterized in that the polymer is also permeable to water and that the mixture also contains 0.1 to 15 wt.% Of an osmotically active, soluble substance to which the polymer is impermeable, the soluble Substance in the form of individual depots with a number average diameter of 1 to 250 ßm > which are dispersed in the polymer in such a way that they are essentially individually surrounded by a polymer layer. 2 • cm IO-8 to 10-12 —-, preferably cm2 • sec • cm Hg 5 x 10-9 to 5 x 10-11, g'Cm cm2 • sec • cm Hg (determined by permeability test according to a modification of the standard ASTM E 96), tensile strengths of 2500 to 70,000 kPa, preferably 3500 to 20,000 kPa, and elongations at break of 10 to 2000%, preferably 200 to 1700%, can be used. Examples of such polymers are commercially available cellulose acetate and its derivatives, partially and completely hydrolyzed ethylene-vinyl acetate copolymers, highly plasticized polyvinyl chloride, homo- and copolymers of vinyl acetate, polyester of acrylic acid and methacrylic acid, polyvinyl alkyl ether, polyvinyl fluoride and silicone polycarbonates. Ethylene-vinyl acetate copolymers are particularly suitable alone or in a mixture with other materials. Of the ethylene-vinyl acetate copolymers, those with a melt index above about 20 g / min. and a vinyl acetate content above about 20%, e.g. from 20 to 45%, preferred. The content of the mixture in the individual components is also important. It is expedient for there to be so much medicament that the desired therapy can be achieved with the size of the device which allows the body part in question. There must also be so much polymer that the depots are essentially individually surrounded by a polymer layer and the mixture is connected to form an integral structure. Finally, 0.1 to 15% by weight of the soluble substance is present, so that the effective surface of the device increases significantly in situ. In most cases the mixture contains 4 to 75% by weight of drug and 20 to 95% by weight of polymer. Smaller amounts of other substances, such as surface-active agents, pigments, stabilizers and the like, can be contained in the mixture if necessary. The mixture preferably contains 5 to 65% by weight of medicament, 30 to 90% by weight of polymer and 0.5 to 5% by weight of soluble substance. The medicament, the polymer and the soluble substance can be mixed with one another by means of customary mixing methods, such as are used for pharmaceuticals, fine chemicals and polymers. The components are usually mixed in solid form and cast, pressed or ground into a suitable structure. If the mixture is first formed into a crude integral mass (such as a sheet or film) rather than the final structure, it can be punched, cut or other commonly used to convert it to its final form. The final shape and size of the device is usually determined by the location of the body in which the device is to be inserted and the therapy for which it is to be used. For example, devices that are to be inserted into the folds of the conjunctiva to release ophthalmics within a period of 1 to 7 days will be of such a shape and size that they can be inserted into the eye and held there. Such devices are usually in the form of thin, disc-shaped, elliptical bodies with a size of 6 to 25 x 4 to 10 x 0.1 to 1 mm. The environment into which the device is placed can be any internal or external body tissue or internal or external body cavity that contains an aqueous medium. Such environments are e.g. B. 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 623 232 2. Device according to claim 1, characterized in that the soluble substance makes up 0.5 to 5% of the mixture. 2nd PATENT CLAIMS 3rd 623 232 see stimulants, tranquilizers, anticonvulsants, muscle relaxants, Parkinson's disease agents, anti-pyretics, anti-inflammatory agents, local anesthetics, spasmolytics, antiulcera, prostaglandins, antimicrobial agents, hormones, estrogenic steroids, progestagenic steroids, e.g. B. for contraception, sympathomimetics, cardiovascular agents, diuretics, antiparasitic agents, antihypertensive agents and ophthalmic agents. In order for the soluble substance to be osmotically active, it must by definition be so readily soluble in water that its aqueous solution on the polymer layer between the depot of the soluble substance and the aqueous environment has an osmotic pressure gradient which is so great that water from the environment is sucked through the layer into the depot. Soluble substances that are able to form saturated solutions with relatively high osmotic pressure gradients are preferred because the depots are blown up faster and the effective surface of the device increases correspondingly faster in situ. Soluble substances capable of generating an osmotic pressure ('n :) in the range from 3000 to 30,000 kPa are particularly suitable. Examples of such soluble compounds are magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, acid potassium phosphate, calcium lactate, magnesium succinate, tartaric acid, soluble carbohydrates such as sorbitol, mannitol, raffinose, glucose, glucose, glucose Lactose, their mixtures, etc. The soluble substance is usually also essentially physiologically and pharmacologically inert. This means that it is non-toxic, has no therapeutic effect and does not cause any significant undesirable side effects. However, ionic therapeutic agents can also be used as soluble substances. In this case, the nonionic drug and the ionic therapeutic agent are administered simultaneously. If desired, the component of the device representing the soluble substance can also be a mixture of a non-therapeutically active soluble substance and an ionic therapeutic agent. The number and size of the depots from the soluble substance is important. In order to achieve a significant increase in the effective surface area of the device, a large number of depots must be available. If the depots are too large or too small, they cannot be easily dispersed in the mixture with a high degree of "single encapsulation", or they cannot absorb so much water that the surrounding polymer layers are blown up. The size of the depot can vary depending on the osmotic activity of the soluble substance, the thickness of the surrounding polymer layers and the physical properties of the polymer. However, the depots must have a number average diameter of 1 to 250 / m, preferably of 1 to 50, m. The polymer component of the mixture expediently has such a tensile strength and elongation at break that the layers encapsulating the depots are blown up by the pressure generated by the water sucked into the depots. The insolubility in water at least during the period of drug delivery enables the polymer to act as a matrix that binds the mixture together to form an integral, intact, solid structure. The water permeability is necessary to allow water to be sucked into the depots. Drug permeability is required so that the drug to be dispensed from the device is dissolved in the polymer and is molecularly distributed by the polymer in the direction of lower thermodynamic activity, i. H. diffuses towards the watery environment. The impermeability to the soluble substance is necessary so that the depots containing the dissolved substance absorb water and are blown up, instead of merely diffusing through the polymer like the drug. Polymers with water permeability of 3. Device according to claim 1, characterized in that the soluble substance is capable of generating an osmotic pressure in the range from 3000 to 30,000 kPa. 4. The device according to claim 1, characterized in that the number-average diameter of the depots is in the range from 1 to 50 [im. 5. The device according to claim 1, characterized in that the soluble substance is sodium chloride. 6. A method for producing devices according to claim 1 by mixing the nonionic drug with the polymer and shaping the mixture thus obtained to form an integral solid structure, characterized in that 0.1 to 15 wt. %, based on the mixture, of the osmotically active, soluble substance incorporated into the mixture in such a way that the individual depots of the soluble substance are essentially individually surrounded by a polymer layer. Uniform (“monolithic”) devices for delayed delivery of drugs or other active substances are known. One type of "monolithic" device consists of a shaped body made from a dispersion of a fine-particle, usually solid drug, which is dispersed in a polymer matrix which the drug is able to pass through by diffusion (see e.g. U.S. Patent No. 3,416,530). In such devices, the polymer matrix can be substantially compact, i.e. not perforated, and be homogeneous. In this case the drug dissolves in the polymer itself and penetrates it. "Monolithic" devices in which the polymer matrix is initially microporous are also known. In these microporous devices, the pores of the matrix contain a liquid or gel-like medium which is permeable to the drug, in which the drug preferably dissolves with respect to the polymer and which it preferably penetrates with respect to the polymer (see, for example, the US Pat Another type of a “monolithic” device for the delayed delivery of medicaments to aqueous environments in bodies, such as the various body cavities of humans, is described in DE-OS No. 2,419,795. These devices consist of a shaped body which is produced from a mixture of individual depots of a medicament or a medicament preparation, which is an osmotically active soluble substance, and a water-impermeable polymer which is impermeable to the medicament. The depots can be made from the pure drug, which in this case is itself an osmotically active soluble substance, or from a mixture of the drug and an additive, e.g. B. an inorganic salt, which is an osmotically active soluble substance. The depots are dispersed in the polymer in such a way that they are essentially individually surrounded or encapsulated by a polymer layer. Such devices deliver the drug by means of an osmotic suction blast mechanism in which the depots, sequentially advancing from the outside inward, soak up water starting at the depots at or near the exposed surface of the device, thereby causing the contents of the depots in question to accumulate dissolves and generates a pressure that is sufficient to blow up the polymer layers surrounding the depots and to allow the delivery of the drug. The device according to the invention is defined in claim 1 and the method according to the invention in claim 6. In the accompanying drawings: 1 is a curve in which the rate of delivery of hydrocortisone is plotted against time for the devices according to Example 1, Fig. 2 is a graph plotting the rate of delivery of hydrocortisone versus time for the devices of Example 2, and Fig. 3 is a graph plotting the rate of release of idoxuridine against time for the devices of Example 3. 1 to 3, the rate at which the drug in question is dispensed is plotted in jig per hour on the ordinate and the time in hours on the abscissa. In the method according to the invention, a mixture of the three components defined in claim 1 is produced and deformed to form the integral solid structure defined in claim 1. The polymer serves as a matrix that connects the components to form an integral structure, the nonionic drug normally being the only therapeutically active substance. The third component, namely the soluble substance, normally does not play a therapeutic role, but is a means by which the effective surface of the device can be increased in situ. All components are therefore extremely important for the functioning of the device. If the drug has a high solubility in water, it may tend to act as an osmotically active soluble substance itself and absorb water. If this is the case, the drug is more likely to be released by the suction-blasting mechanism, which was briefly described above and in detail in DE-OS No. 2,419,795, than by diffusion through the polymer. If the drug has a water solubility of less than 200 ppm, it cannot quickly release from the polymer surface. The rate of release then depends on the mixing in the interface instead of the rate of diffusion through the polymer. Preferably the drug has a water solubility in the range of 300 to 5000 ppm. The type of drug depends on the therapy for which the device is intended. Drugs that have a local effect at the site of administration or drugs that have a systemic effect at a site remote from the site of administration can be used. These drugs include inorganic and organic compounds, e.g. B. hypnotics, sedatives, psychological 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 4th the eye, the vagina, the uterus, the gastrointestinal tract, the circulatory system and the muscle tissue. When the device is placed in one of these environments, drug delivery from the device begins. As mentioned above, this delivery involves the dissolution of the drug in the polymer and its diffusion through the polymer to the surface of the device that is in contact with the environment. The distance that the drug must travel through the polymer before it reaches such a surface affects the rate of release. The absorption of water through the depots of the soluble substance also begins, one after the other from the outside inwards, starting with the depots that are on or closest to the outer surface of the device. When water is sucked up from a depot, the surrounding layer of the polymer swells first and is then blown up when its cohesive strength is exceeded by the pressure generated by the sucked-up water. After blasting, the soluble substance is quickly released from the device and leaves a cavity at the location of the depot. This cavity is also quickly filled by the aqueous medium, which is then sucked up by the next adjacent depot, etc. The water absorption of a depot is not entirely dependent on the bursting of the neighboring depots further away, so that it is possible for water to get into one Depot is sucked in before neighboring depots located further outside are blown up. The effect of such successive blasting is that the device forms inner pores and channels, the surfaces of which represent areas from which the drug can be released from the polymer to the medium. This generally shortens the distance that the drug must travel through the polymer before it is released. The formation of the internal pores and channels is expediently quick in relation to the total duration of the drug delivery. Preferably, this formation is substantially complete within the first 1 to 20% of the total therapeutic life of the device. The term "effective surface" as used herein means the surface of the device from which the drug can be released from the polymer to the aqueous medium. When the device is first placed in the environment, its effective surface is equal to the surfaces that define its outside. As described above, however, the successive blasting of the deposits of the soluble substance creates additional surfaces from which the medicament can be released. So during the duration of the detonation of the depots, i.e. until the point at which all depots are blown up, the effective surface continuously increases, and at any given point in time (t) during this period the effective surface is approximately equal to the sum of the surface bounding the outside of the device and that Surface through which the interconnected cavities caused by the blasting are limited. The difference between the effective surface at the beginning of the blasting and the effective surface at the end of the blasting depends on the size and the number of depots and on the type of polymer. If the effective surface area increases in situ in this way. this affects the delivery of the drug in three ways: the delivery rate is increased, the duration of delivery for a given total amount of the drug is shortened, and the constancy of the drug delivery rate may increase. These effects are advantageous in cases where higher drug delivery rates are desired than can be achieved with simple monolithic devices that act through diffusion. It may also be more economical to achieve higher delivery rates in this way than by increasing the concentration of the drug. In the latter case, considerable amounts of the drug can remain in the device at the end of the therapy period, so that the drug is not fully used.