DE1617724A1 - Process for the production of drugs with delayed action - Google Patents

Description

Joseph Campau Avenue at the River, Detroit 32 »Michigan, USA

concerning -

"Process for the preparation of drugs with delayed release ^11. -.; - .. ^: ^

The invention relates to drugs "in-novel." Jorin and composition based on pharmaceutical and other areas have valuable advantages. In particular The invention relates to manufacture novel dosage forms with controlled release for "internal administration of medication *

• The evaluation of the! Principle of the "controlled", in particular the "time-controlled ¹ * release, as it is realized, for example, through the usual! Forms of the gradual, delayed release of the prolonged or repeated effect or the; / issen Dösierungenj, is always in the last drive

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_ 2 -

become more important. These dosage forms have various advantages as they can be "used" by conventional methods It was not possible to achieve an approximately constant blood level for the blood with a single administration today Maintain the drug for 8 to 12 hours, with the peaks and minima in the blueprint balanced, as they always occurred up to now when individual doses were administered in more or less frequent intervals. It has it has been shown that the patient responds much better to certain drugs and that the occurrence of HTebea- ■ Effects is diminished when the drugs are administered in this novel way. Except for one Cost savings, this system is above all better adapted to the needs of the patient, in particular, if the blood level is steady over the full 24-hour period must be maintained.

In order to achieve the gradual, To achieve a delayed effect, 2 basic mechanisms for the release of active substances were used, namely the release by digestion and that by leaching, whereby the most diverse modifications are possible.

If the digestive mechanism is to be switched on to release the drug, then the drug is either wrapped or incorporated in a fine distribution into a substance that digests slowly in the digestive tract

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or is dispersed. As the digestive process progresses, the medicine then becomes available for the body fluids ■ available. The extent and the speed with which it becomes available is a puncture of speed, with which the slowly dispersible cover or carrier substance ■ is digested. Although products that have this mechanism comes to! in the form: of compressed, coated or multilayered! tablets and as from a shell Encapsulated granules or pills are available, all of these forms are not the various physiological conditions in the patient to whom the Medicines are administered in a fair manner. B. on gastric mobility, enzymatic © activity and hydrogen ion concentration. The ability of the individual patient to digest insoluble substances, is an undisputed fact and it follows that a dosage form which does not take this into account is necessarily must have a different effect. The mentioned inequality between the individual patients in terms of release speed is a serious one Restrictions on the use of dosage forms based on this mechanism. It is · of the greatest Importance of digestion in 1, line in the top InteBtinal - section takes place during the_absorption can take place throughout the intestinal tract.

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The based on leaching release mechanism can thereby be realized that by coating the drug with a film, a part of which is at least soluble and is pore-free, through which can diffuse the agent _s or by incorporating the drug in an insoluble matrix, from which diffuses them out. The leaching mechanism does not depend on digestive processes, but it still has a serious disadvantage. The rate of release is a function of the surface area exposed to the leachate and the distance over which the drug must diffuse to become available to the body fluids. It follows from this that the extent and the speed of the release at a given time after ingestion each have a different value and decrease more and more from the time of ingestion. So if you want to maintain the necessary blood level for 8 or 12 hours, a major overdose must be present during the first time after ingestion is not fully released. The medicament is therefore either released too rapidly into the gastrointestinal tract to be physiologically available, or there is "the risk that the repeated administration of such products will have the effect that the agent will accumulate in the tissues and that side effects will occur.

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A further classification of the medicaments with controlled release can take place according to product types The main names here are tablets and capsules with controlled release that have a larger number of Contain small seeds, pills or granules. Apart from the mechanism of action, they are made of granules Cores, pearls "or pills made products preferred because due to their larger surface area Release takes place completely uniformly and the quality control is easy small lights a more uniform, reproducible Achieve throughput through the gastrointestinal tract than at a single large tablet, 0;

With the small particles you can also choose between. see two different classes or types of distinction between themselves. One type consists of shaped, cast or tabletted particles in which the active agent is finely divided in a solid matrix. Although this embodiment has the goal of administering a larger number of particles such products are “irrespective of whether they are used for release by the digestive or the leaching mechanism, and are particularly known for being initially; Release the drug quickly, but often do not allow it to fully take effect within the 8 or 12 hour period, "\;^:;

The second of the above-mentioned embodiments, in small particles with a coating, generally this is .sich very small sugar granules, which are initially with the drug and subsequently coated with a film which is partially permeable to water is _e The manufacturing method for such particles has several other disadvantages besides the high cost · When the drug is applied to small granules, the fundamental technical limitations of the manufacturing process inevitably result in the small core being coated with different amounts of drug at each time. The coatings are usually applied in layers that alternate with the drug layers. Due to the limited dimensions, only small doses of drugs can be used and, in addition, the release mechanism does not work safely _{or similarly}

Compared to this prior art, the invention provides a larger number of dosage units Form of coated pearls, which the drugφ Release at a uniform rate over a period of 8 to 12 hours, with the rate of release sufficient to ensure that an appropriate blood level is maintained over this entire period.

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Another object of the invention is to provide a controlled release dosage form "which functions independently of the various physiological conditions of the individual patient, _{or the like}

In the agents according to the invention, a complete release of the drug due to the in each Dosage unit occurring internal pressure »

In their dosage-appropriate form, the medicaments according to the invention comprise a larger number of coated pearls, each of which is relative contains a high proportion of medicinal products. In each of coated pearls is the ratio of drug content constant and invariably uniform to the weight of the pearl

The dosages according to the invention with controlled Release can be used for medicines that either relatively well or relatively poorly soluble in the physiological fluids are.

The invention is explained in more detail with reference to the drawing i

2QS8UM583

Figo 1 shows a single bead that contains the drug

- Contains and is provided with a coating, which the latter partially detached. is to show the interior of the pearl j

Fig. 2 shows a pearl in which the coating has torn is]

Pig. 3 is a top plan view of a drug bead after tearing the coating, which has already been partially stripped off in the picture.

Fig. 1 shows a unit 1 in the form of a spherical Pearl 2 with a smooth surface, which is enclosed by a tight-fitting, easily tearable shell in the form of a film coating 3 which is inert to the body fluids, i.e. the coating is neither toxic noeh soluble in body fluid; he is indigestible, but permeable to water that diffuses through. The pearl or the small core 2 in turn consists of a water-swellable, medicated colloid, i.e. a colloidal substance that contains an or contains several medicinal products that are compatible with the colloid « The medicament can either be in dissolved form or, as shown in FIG. 1, in the form of dispersing

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- 9 - · '.' ■■■■. ■. -Λ. ■■■ -

'Fixed marriages 4 exist. Hie aarge posed Unit 1 comes after ingestion and immediately after Entry into the gastrointestinal tract incontact with the water-containing body fluid that flows in the course of the tent gradually through the coating 3 into the interior of the core penetrates, which, as noted, is swellable in water Colloid contains "Under the influence of the penetrating Water, this core begins immediately to the water absorb and swell «. With the port view of the During the absorption process, the colloid swells more and more, the more water diffuses through the shell into the core When the swelling pressure of the colloid has reached the Kphäsionskraf.t of the coating, this will tear and as a result of the tearing, which usually occurs suddenly the drug content of the nucleus in direct »" "- contact with the surrounding body fluid and the body tissue, whereupon the absorption and uptake of the drug in the form of the normal physiological process takes place without further delay

: "? ig ·· 2 shows a pearl 1 that has been around for a long time is under the influence of the surrounding water * so that the Shell 5 is already torn and has a larger opening has, which is partially hemmed in by irregular edges 5, and through which the inner pearl 2 is visible

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isto The state shown in the picture is typical for the case in which the liquid flowing around the coating 3 is in motion ₀

In contrast, Figo 3 shows a state that occurs when the liquid surrounding the coating is relatively at rest o

It is a special feature of the embodiment according to the invention that the bead 2 under the influence of the water that has diffused through the shell 3 swilitates the envelope is torn by the swelling "the release of the drug takes place, therefore, although very rapidly (ie, ₀ within a few minutes after the break), but only trliTtt considerably later than the time of administration. It is also important and advantageous that the release of the medicament is only dependent on the presence of water and not on any enzyme action, a certain pH value, the rapidity of the digestion rate or on. any mechanical abrasion, etc. Dis is

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This is advantageous insofar as water is present in all individuals, the vapor pressure of which, as a puncture of the temperature, hardly differs in the individual individuals c

Apart from various aspects of the coating and the bead 3 to be described later it is precisely the interaction between the feasible Core and the water-permeable coating, which gives the excellent results in terms of a controlled

he
Release of the drug / possible.

According to the invention, the carrier substance for the bead 2 is the most diverse colloidal substances suitable A particularly useful and therefore preferred one Gelatine is a colloid, but other colloids can also be used in addition to or instead of gelatine. These include starch, starch phosphate, zein, gum arabic, agar, albumin, tragacanth and colloid mixtures of e.g. gelatin and starch. The amount or the relative proportion of the colloid in the individual bead can be quite different. But there must be so much in every pail Colloid that be present in the absorption of water over time such a swelling pressure is reached that '

the cohesive force of the coating film is overcome *

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The choice of the colloid is not decisive if it only has a corresponding water absorption capacity - and swells in the process. The colloid substance can optionally contain plasticizers such as sorbitol, glycerine and the like. The colloid used in the present dosage forms usually in dry form or at least in a form that showed a significant absorption capacity for water in the case of gelatin, for example the commercial varieties that normally have a water content of about 11 $ ₀ are suitable in certain cases, particularly when maximum stability to the drug content is to be achieved, the water content is preferably lower, d _o h _e it is less than $ 11 down to 1 -

As already mentioned, according to the invention, the colloidal material contains one or more compatible drugs, The drug (s) can either be liquid or solid in the colloid mass, depending on your requirements Phase. In an embodiment which is described in more detail below, the medicament lies or is dissolved dispersed in warm liquid gelatin before, and the liquid is through an opening into a non-turbulent Squeezed stream of a liquid coolant, so

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that the gelatin "divides into discrete, smooth, spherical solid beads in which the drug is uniformly dissolved or dispersed * The pellets are then dried to make them hygroscopic * Within a certain batch - each individual bead contains the same amount of drug , which is always homogeneously distributed _0. ^f

It is a particularly advantageous feature of the invention that the pearls contain significantly more drugs, based on the weight per dosage unit, than the usual delayed release agents, which consist of a larger number of individual granules or delayed release pills Pearls may contain more than 50% of their weight in medicament. In this connection it should be pointed out that the drying of the pearls after their formation ^{should take place at or below the "stickiness point 11} ", ie at a temperature at which the individual should be subjected to cooling perlchen not stick to each other. This Klebrigkeitstempera- / door depends to a counter-rotating sense of the Arzneimittelkonzentratiön, i.e. _e. when the, Perlohen have a relatively high Arzneimittelkoiizentration, the temperature at which they become sticky is low in general, and

drying must therefore be carried out at relatively low levels Temperatures, e.g. in the region of 10 - 15 ° C or go deeper «»

A wide variety of medicaments can be incorporated into the dosage forms according to the invention and their concentration can be within a wide range vary. Generally speaking, one must use drugs that are in the appropriate concentration are compatible with the colloidal filling material, i.e. » which do not affect the desired swelling properties of the colloid, examples of drugs, for which this condition applies, analeptics such as pentylenetetmeol and ephedrine} stimulants for the central nervous system such as amphetamine, bethanechol, Ueostigmine, 2-dimethylamino-ethanol tartrate, captodiamine and Mepazinj anorectic agents, such as phenmetrazine, Bioethylpropion and phenylbutylamine; Antihistamines, like Thonzylamine hydrochloride, diphenhydramine hydrochloride, Bromodiphenhydramine hydrochloride and chlorpheniramine maleate | anti-inflammatories and analgesics, such as acetylsalicylic acid, Aoetophenetidine and phenylbutazine; Anticonvulsants, such as diphenylhydantoin sodium, trimethadione, phensuximide, pamidon, methsuximide and ethsuximidj antimicrobiale Agents such as antibiotics, sulfonamides, etc .;

in anti-parasitic agents, such as Amodiachii hydrochloride,

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Biallylamicolhydrochlorid, ^{Chinacrinhydrοchlorid;} Ghlorochine phosphate and pyrvinium pamoate; and depressants for the central nervous system or "TranquiLiz ^ er", such as Chlorpromazinj Meprobamat, Benactyzin, Hydroxyzine, Äthchlorvynol and Ectylurea. Of course, the possibilities are not exhausted

The coating film used for the pearls _x according to the invention is a substance which is inert to the body fluid, ie non-toxic, insoluble and indigestible, but which is permeable to the penetration of water by diffusion. The expression "indigestible" is to be understood as film-forming coating materials which are either completely indigestible or at least resistant to digestion, ie they must not at all or at most completely before the shell bursts as intended and the drug is released from the bead little amenable to digestion. Some of the coating materials listed below are perhaps not, completely indigestible, but withstand digestion to a sufficient extent and are therefore preferably used together with one or more other more inert substances so that the envelope as a whole has an adjustable resistance to attack and digestion opposed. Incidentally, some of these over-

tensile fabrics more suitable for forming films than others, so that if a given coating substance should have particularly good film-forming properties, this improvement can be achieved by a substance is used which has particularly good film properties. In general it can be said that the coating can be produced with the help of substances that form a relatively thin, coherent, but tearable film opposite the is resistant to leaching or digestion by body fluids < >

For this purpose, very general substances are used that form a plastic film. Among the large number of such film formers, the following types of plastic base materials are to be mentioned: Cellulose substances, such as ethyl cellulose and ethyl hydroxyethyl cellulose, cellulose esters such as cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate and cellulose nitrate ι Fluorkohlenwasserstoffharae, particularly Fluoräthylenharze as Tetrafluoräthylen- and Chlortrifluoräthylenharze} polyamide Epoxyharze5 synthetic rubber such as polychloroprene and butadiene, isoprene Styresae, polysulfide, acrylic, polybutadiene, and poly urethane rubber 1 Vinylöhloridharze, vinyl chloride-vinyl acetate resins, vinyl chloride -Vinylidene chloride copolymers and vinylidene chloride aoryl nitrile resinsi Acrylates and methacrylates |

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Epiehror ^ hydrinbisphenolharze; Polyamide resins and polyamide ^ epoxy ^ and polysulfide ^ epoxy resins; Alkyd resins (combinations of phthalic anhydride and polyhydric alcohols)? .Furanli resins; -Silicon-on ».'- SiliGon-Alkyd— ■ and silicone phenol resins or» elastomers; Cümaron resins; styrene and styrene butadiene resins; Hydrocarbyl. "And terpene resins, and ^u reth.ane * Preference include Ithyloellülose, Chlortrifluoräthylen- (CTFE) resins ,: as" Kel-esoo "letrafluorätliylen- (TFE) resins ^ as" Teflon 30 "and Yinylchlorid -irinylidene chloride ^ -opolymerisatej such as saran resin .1-220 and saran latex! '- 122A15 «

Curing bzwo the polymerization of plastics, so far as this is necessary for the production of the finished wrapping is carried ^ _r, as will be described, on. The usual way Ό The mixture for producing the outer shell can also contain a coating film-modifying agent in order to permeate the desired degree of water. to ensure nonchalance in the finished 3? ilm. Among the many substances that can be used for the latter purpose, the following may be mentioned: waxes of mineral, vegetable or animal origin; Esters of higher (about G ₁ ^ o * ^er higher) fatty acids or higher (about G ₁₂ or higher) fatty alcohols including the esters of such alcohols with such acids; hardened oils, e.g. HizinuBölj Glycerinestep of the mentioned acids and acetylated Monoglycerlde ^ ■: "

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The film-forming coating material can be applied by any method as long as this results in a continuous film of substantially uniform thickness The coating agent is poured or sprayed in a suitable solvent over the moving pearls. It is important to ensure that each pearl is uniformly coated and that no non-uniform film coatings arise, as would happen, for example, if the pearls are connected _o The coated pearls are dried with warm air. When the appropriate film thickness has been reached, the coated beads are, if necessary, heat-cured (drying in the air or in the oven), polished and, if desired, treated further. are ,, can also be applied _o A preferred method is the last-mentioned coating in the vertical spray as ben described in U.S. Patentsehrif described 2,648,609 and 2,799,241. In this method the article to be coated beads are ν in a column by means of a turbulent air flow in the balance maintained, while a finely sprayed solution -

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"or dispersion of the coating agent from below is sprayed into the column above, so that in it contained pearls uniformly coated: and at the same time o If the coating has hardened as necessary, it can be used in conjunction with the irοcfeen process or to be carried out afterwards «, The most diverse ! Solvents and their mixtures can be used for the preparation the solutions or dispersions of the coating agent are used «. It is important that the solvents or dispersants can easily be removed by evaporation or other known means, which is why they - ■ -. should preferably be relatively volatile and have a low viscosity, some preferred solvents for this purpose are for example Water, halogenated hydrocarbons, such as (drichlorethylene, Methylene chloride, carbon tetrachloride or Chloroform; Alcohols such as absolute alcohol, isopropanol or methanol; low molecular weight esters such as ethyl and Amyl acetate or ketones such as acetone, 2-butanone and the like performing the coating process one can deja resistance of the coating film against cracking under the Swelling pressure as well as its permeability for water vapor vary by adding that or the coating agents, and the Selects the thickness of the coating accordingly. In this way by varying the coating agent and the film thickness one can adjust the time at which the medicament after ',

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ingestion is released «The relationship between The factors mentioned can be mathematically patched up are based on the following equation showing the release phenomenon as a two-step mechanism on the diffusion of water vapor and the swelling of the colloid, shows:

t = Kd ² + K ¹

where t is the time to release the drug Exposure time,

No constant that depends on the type of coating material,
K 'the time that the uncoated colloid

needs to release the drug and d means the thickness of the coating film.

Based on the constants for the coating material and the colloid, which can be determined by the usual investigations, the time in which the release of medication taken internally takes place can be predicted and controlled by one for the given colloid material and the coating agent selects appropriate thickness for the coating film. The size of the Perlchens, d _o h. the diameter of the core can also be varied, but a modification of this size does not significantly affect the release time.

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Obi-eich according to the invention zimächat an uncovered one Bead of sufficient size 'provided as a unit which inherently contains the full desired dosage of drug, there is a preferred one Formation in a plurality of small ones coated pearls of a uniform nature (i.e. uniform in terms of the pearl size, on the film coating, on the thickness of the pilm, etc. ”) or in a Konfbinatiön from-among themselves different kinds, if applicable are contained in a pharmaceutical carrier ^ like a hard or soft capsule, a suppository, a non-aqueous syrup or other pharmaceutical carrier, possibly together with binding agents * Each of the coated pearls then contains a partial dose and can be used in various ways are varied o The main variation possibilities extend to the following 2 actuators:

a) in the manner of the Pilmuberzugö, '' ■ '. b) on the film dioka,. ro) on the type of drug,

d) on the nature of the colloidal substance

and endlioh =

θ) to the size Tizwo the öesamtObe rf lache

of the covered pearls. ;

Accordingly, if the dosage contains a plurality of coated Pearls with individual variations regarding

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the release of the drug, ie if it is a multiple dose, it is up to you to control the release accordingly. For this purpose, for example, a non-enteral gelatin capsule is administered orally which contains a large number of coated pearls, in which the material or the thickness of the coatings is appropriately matched. The capsule enclosing the pearls usually dissolves in about 10 to 30 minutes and the differently adjusted pearls are then directly exposed to the body fluid. Under these conditions, the envelopes of the individual pearls burst open one after the other, depending on the thickness and type of the pilm cover "that envelops the individual pearl. Thus, in a precisely adjustable manner, some pearls, which have a thin or a relatively well permeable shell, can already be in one burst early and cause rapid medication, while others with a thicker or less water-permeable shell remain intact for a long time and only later individually and progressively burst from time to time, depending on the nature and thickness of their shell one obtains a continuous, uniform and well-controlled medication. By varying accordingly the Wasaerdurohlässigkeit of the film coatings in a progressive series over a predetermined range, as is done, the bursting of the shells allmählioh and at equal intervals so that a continuous were to release the drug.

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he follows. Such Mehrfachdoeierungen can be mixed with the coated also a number of uncoated pearls which take effect immediately upon administration.

The invention is illustrated in more detail by the examples.

Production "of uncoated colloidal beads example 1

(a) Composition of the colloid body:

Pig skin gelatin, Bloom 270 10.0 kg

least. Water 34.0 1

Diphenhydramine hydrochloride 40 kg

Glycerine 0.5 1

The gelatin is mixed with 25 l of water and left swell overnight. The hydrated gelatin is then heated to 70 °, whereupon 9 liters of water are added to it while stirring. which contain the diphenhydramine hydrochloride. The glycerol is also heated to 70 ° and stirring admitted. The resulting colloid mixture has a viscosity of 1300 cps at 70 ° as indicated on the Brookfield Viscometer

with
can be determined with a spindle 2 at 30 rev / min. The mixture is then converted into solid beads with the aid of a device for producing beads. Briefly, this improved type device consists of a reservoir for the colloid material to be processed, connected by guide means to a manifold, the latter ending in a series of 20 parallel hypodermic needles No. 22 for expelling the colloid; Pump means are provided for delivering the liquid colloid to the conduit at the desired rate and pressure. In this way, the liquid colloid can with one. adjustable speed from the reservoir into the distribution line and from there through the needles and out of their openings liinauGgG. The apparatus further includes one

2 0 9 8 U / 1 5 G 3 _BAD ORIGINAL

inclined trough, over which a cooling liquid is passed with the help of pumping and cooling devices with "certain speed, strength and temperature" which does not 'mix' with the liquid colloid. The threads are arranged in a horizontal row above and at right angles to the The direction of flow of the liquid coolant and extend vertically downwards in such a way that their opening almost touches the surface of the liquid and all are at the same distance from this surface and conduct it in noise from a plurality of liquid threads into the coolant flow. Petroleum ether is used as the coolant, which is kept at 10 ° C and flows with a linear velocity of 50 cm / sec without turbulence. The thickness of the coolant flow is> about 1 1 / 2 cm, the width of the trough 20 cm and the angle of inclination to the horizontal 20 ° the liquid colloid emerges in a total amount of voi / about 30 l per hour, the speed of the liquid colloid, with; The amount of water it enters the coolant flow is approximately equal to ITuIl relative to this flow, but it is immediately distributed in the coolant and carried along by it at increasing speed until the coolant and colloid flow along at about the same speed. When this happens, the colloid flow becomes dynamically unstable and breaks up into uniform spheres or pearls, which are supported by the

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Coolant flow are carried along and harden in the process. The coolant stream with the colloidal beads is then collected in a receptacle. The beads are then separated from the coolant and to the extent initially dried at 10 ° that they contain 5% water, whereupon it to a water content of 1 to fo further dried at 45th This gives about 11 kg of dried colloidal beads in the size range from 590 to 840 / U, which contain about 28% by weight of uniformly distributed diphenhydramine hydrochloride.

If necessary, other methods can of course be used used to shape the colloidal beads; for example you can put the liquid colloid in a vertical column of air a drop.

(b) For the production of similar colloidal beads that differ only in terms of the percentage of medicinal products, the same colloidal body and procedure as in (a) above is used, except that the relative Amount of incorporated diphenhydramine hydrochloride is changed as desired. When incorporating this drug into the colloid mixture must be ensured that a sufficient Amount of water is used so that complete dissolution of the diphenhydramine hydrochloride occurs. The total amount of water which is necessary for the preparation of the Kolloidgeraisch.es is in essentially kept constant, so that you get the necessary

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Preserves viscosity of the mixture. If one wants to Kolloidperlehen 5 fo DipheTUiydraminhydrochlorid prepare, one bedeient to the procedure of Example 1 (a), but "using the following starting materials:

Gelatin - 6.0 kg

least. Water 22.0 1

Diphenhydratin hydrochloride 0.3 kg sorbitol, 70 fo in water, 1.0 1 '

In a "special implementation, four To dampen approaches from these starting materials separately Processed pearls, which were then collected and dried; the finished pearls showed the following size distribution:

horny size weight -fo

1.0-1.7 mm. 38.0

0.8 -I ₁ OmD. 53.5

0.6-0.8 mm 23.2

0.25-0.6 mm - ■.;. "= 5.3

Similarly, colloidal pearls were made with a higher proportion of pharmaceuticals produced, using the following raw materials:

Gelatine, SO ^ -free, type P 1.0kg Diphenhydramine hydrochloride 1.5 kg

Glycerin "; 0.25 kg

Water 3.0 1

The gelatin is hydrated in 2 liters of water, the third

Liters of water are used to dissolve the hydrate hydrate of hydrochloride

iAD ORIGINAL

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a?

to solve. The yield is 2.35 kg of dry pearls
(Water content 1 fo) , which contain $ 52.3 diphenhydramine.

Example 2 - - ■■

Gelatin 0.9 kg

3-sulfanilamido-6-methoxy-

pyridazine (fine powder). 0.45 kg

Sorbitol, $ 70> 0.1 kg in water

Water 2.4 1

The gelatin is first mixed with 900 cm of water at room temperature Swollen for 3 hours. The hydrated mass is then melted in the heat and 1000 cm Water containing the pyridazine in the form of a slurry contains, added. The melt is kept at 70 ° and mixed well to ensure a completely even distribution

■ 5
to reach. The sorbitol is dissolved in 500 cm of water and the solution is stirred into the suspension melt. The mixture is then prepared using the method described in Example 1 (a)
Process described on small, dry, solid pearls or spheres processed. The individual pearls contain about 29% by weight of pyridazine.

This example shows the production of colloidal beads, which are a water-insoluble medicament in the form of a
Suspension contained in the colloid body. Instead of the above
Pyridazine mentioned can, other water-insoluble drugs or mixtures thereof, especially in proportion

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high-melting agents (ζ. B. chloramphenicol, diphenhydramine salicylate, sulfaguanidine, dimeihydrinate and the like. for the preparation of appropriate suspensions can be used.

Example 5 "

Gelatine 0.45kg F-methyl-Λ-methyl-o (-phenyl-

suceinimide, crystalline 0.45kg

Sorbitol, 70 % in lasser 0.05 kg

Water Qy9 1

The gelatin is in 450 om water "at room temperature Curled up for 5 hours. The hydrated mass then becomes Tritter heating melted and the suecinimide added. That resulting mixture becomes strong as long as it is hot: (75 G) stirred, so that a finely divided emulsion of the melted Succinimids arise. Now the sorbitol is placed in 450 cm of water admixed 'and the resulting emulsion is divided into small, transferred dry, solid pearls or globules, why that The procedure described in Example I (a) is used. DXe individual beads contain approximately 45% by weight of suecinimide.

This example shows the production of, Eollpidperlchen, a water-insoluble drug in the form of an emulsion contained in the colloidal body. Instead of the above Succinimidgi can use other water-resistant medicinal products (e.g. liquid or low-melting drugs, such as phensucoinimide

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Ethsuccinimide
and) or chambers from it for the production of

appropriate emulsions are used.

Example 4

Gelatin 2.0 kg

2 ~ i) iäthylamino-2-methyl-propio-

phenone, nitrate 1.0 kg

Glycerin 0.1 kg

Water 8.0 1

The gelatin is mixed with 4 l of water at room temperature 3 Swollen hours and the hydrated gelatin then heated to 70 ° »The 2-dimethylamino ~ 2-methylpropiophenone nitrate is dissolved in 1 l of water and added to the heated gelatin with stirring, whereupon the glycerine and another 3 l of hot Water can be added while maintaining the temperature at about. The resulting colloid mixture is then using the procedure described in Example 1 (a) processed into dry, solid beads or spheres which Contains 27 wt .- # nitrate salt. This example shows the Manufacture of colloidal pearls, which are water-soluble Drug included, using other water-soluble Medicines or medicinal products mixed in place of the nitrate salt used above can take similar forms share. As water-soluble substances, instead of nitrate · »" salt can occur, such as diamine hydrochloride, chlorine diphosphate, soluble acetylsalioic acid compounds and; the like.

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example

Gelatin 6.0 kg

Methylene blue ~ 0.1 kg

Sorbitol, 70 fo in water 1 kg

Water . 27 T

The gelatine is swollen in 15 liters of water at room temperature. The hydrated mass is then heated to 70 and the methylene blue in aqueous solution (100 g of methylene blue in 2 l of water) is added. The sorbitol solution and 10 l of water are then added with stirring and heating in order to keep the temperature at 70 °. The resulting colloid solution is converted into small, dry, solid colloid beads according to Example 4 (a). The individual pearls contain about 1.5% by weight of methylene blue.

Production of coated Kollold pearls

Example 6 /,.

2 kg of dried gelatin pearls of about 0.8 to 1.0 mm Diameter with a content of 5 wt .-? S diphenhydramine hydrochloride, manufactured according to example 1 (b), are placed in a coating chamber of a Wurster coating apparatus (described in U.S. Patent 2,648,609) and suspended or fluidized in the chamber by means of a turbulent air jet with a. Flow velocity of about 1925 dm / min. The entry temperature of the air is

20981A / 1563

kept at 32 G, the outlet temperature at 19 C. In the Chamber is now filled with compressed air under a spray pressure of 4 »9 kg / cm sprayed a coating solution, which consists of 500 g of ethyl - Cellulose (10 cps) dissolved in 5 liters of a solvent equal parts of chloroform and anhydrous ethanol,

3 sprays. The total volume of the solution is 54-00 cm and theirs Viscosity 1-2 cps at 21 ° G. The solution is made with a sprayed at a constant speed of about 32 cm / min. The total time for coating and drying is 2 hours 45 minutes after which the coated beads (approximately 2950 g) are removed from the chamber. One poses in an analogous way the same pearls with a thinner coating. A product for the controlled release of drugs that is set in this way is that it releases the drug within 8 to 12 hours in vivo, is achieved by mixing a series of such drugs encased pearls, each of which has a different film thickness, and encased in a common capsule.

To produce the .Filmhulle you can use the same process also applies to other filra-forming substances use. Examples are shown in the table below given, from which the influence of the film material concerned it is evident on the release time.

20981471583

■ si

Coating film

! solvent coating

fflittelkonzon * - concentration (Wt / YoI)

Release time for $ 50 I ^ heiihydraminliydro- · chloride in h

Cellulose acetate

butvrat (17 $> Buty- 2-butanone-

ryl) acetone (1: 4)

Sranlatex ***

water

Ethyl cellulose,
Castor wax, paraffin (9: 10: 1) chloroform ',

Ethyl cellulose

Chloroform, anhydrous ethanol (1: 1)

6 10

20 10

9 * 20 **

.3.5 *.

for pearls with 20 wt. 5 & coating
for pe riehen with a 10 wt .-? £ coating
Vinyl chloride-vinyliaene chloride copolymer F-122AT5

Example 7

2 kg of dried gelatin beads of about 0.8 - 1.5 mm
Diameters containing 27% by weight of 2-diethylamino-2-methylpropiophenone nitrate and prepared according to Example 4 are introduced into the Wurster coating apparatus described above and there with a turbulent air flow at a speed of 1700 dm / min treated. The compressed air is introduced at about 52 ° 0 and flows off at around JT ⁰ ° C. With

2
Using compressed air under a spray pressure of 4.2 kg / cm, a coating solution is sprayed into the chamber of the device, which consists of 300 g of ethyl cellulose (10 cps), 60 g of hydrogenated castor oil and 3 g of castor oil, dissolved in 4 l of a solvent the end
equal parts chloroform and alcohol, there is »The solution

209814/15

is sprayed at a constant speed of about 44 cm / min. In order to control the growth of the coating, 50 g of the pearls are removed from the chamber when the coating thickness has increased by 2.5% by weight (based on the weight of the uncoated pearl). This leads to samples - in which the coating made up 2.5 ^c f <* or 5 »0 % or 7» 5 i> or 10 5 »of the weight of the uncoated pearl. The coating of the pearls is continued until all of the coating solution is used up, at which point the drying process begins. The total time for coating and drying is 95 minutes.

Example 8

2 kg of dried gelatin beads about 0.8 to 1.0 mm in diameter with a content of 1.5% by weight methylene blue, prepared analogously to Example 5, are introduced into a Wurster device as above and there with a turbulent air jet treated. Supply and discharge temperature of the air &&& · correspond to the values in Example 6. Fun the chamber under a spray pressure of approximately _e 5 kg / cm 6.4 1 of a solution of 5 wt .- $ ethyl cellulose (10 cps) in equal parts by volume of absolute alcohol and chloroform at a constant rate of about 15 era / min. For testing purposes, sample beads are taken from the chamber periodically as the coating grows, the first sample being taken when the weight of the coating is 2 Grew _e -? 6 (related

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on the weight of the uncoated pearls). The further samples are always taken when the coating has increased by $ 2, in particular between 4 and $ by weight for the coating Pearls are removed from the device for drying. The yield, apart from the samples taken, is about 2.2 kg of freely moving, coated pearls. The outer shell of the pearls is extremely thin in relation to their overall size. Thus, for example, have beads of about 840 / U diameter, carrying a coating of 16 wt .- $, an average of about 28 Mlmdicke / ^U. Λ

Example 9

You work with the same pearls and with the same Coating procedure as in Example 8 but uses one Coating solution of 30 g of ethyl cellulose (10 cps), 30 g of hydrogenated Castor oil and 3 g non-hydrogenated castor oil dissolved in 4 1 of a solvent made of equal 0? parts Ohloroform and alcohol » The following display times were used for the various coating thicknesses noted

Coating weight 15 minutes 60 minutes 2 hours 4 hours 6 hours Sh

2.5 1 ° . 1, Φ $ 46.0? Δ 88.5 ^ 100% 100 ^ $ 100

5.0 fo 0 4.7 $ 21M 65.3? Ί 87.7fo 96.2 ^o / o

7.5 ίο 0 0 ■■. "". 3.33 ^ 1.6.2 ^ 39.0 $ 70.5 $

20 981 4 / 1SS3

- Ψτ - Sb

The table provides a concise overview of the release process for different film thicknesses. she shows also that by appropriate. Choice of coated pearls the course of the medication can be largely influenced, The user is free to choose pearls with the same film thickness or a selection of pearls coated with different thicknesses apply.

Production of dosages with a controlled release time Example 10

For the purpose of multiple dosing with continuous release of the drug (in the present case of methylene blue) with loose beads, equal weights (2 g) of the samples prepared according to Example 8 with a coating weight of 4 to 16% were combined. The mixture so prepared can be administered orally, either loosely or in any bound form. If capsules are used, one capsule contains ITr. 0 with hard shell about 0.4 g of the mixture.

When examining the release of the drug in vitro, a sample of the mixed product is a continuous one Effect for up to 8 hours; the experiments were carried out in water and in 2 different artificially prepared body fluids performed and showed the following results:

2098 14/1563

■■ ν.- ■ »■; ■■,; .; ■ - · .; : /: ■■

Approved medicinal product ·, total amount- in time (h) water gastric juice. * i? 3S! Ä &

1 7 7 7

2 16 16 ■ - ■■ ._ ■ 16

3 30 31 30

4 43 42 44

5 '55 55 54

6 67 66 66

7 77 77 76

8 85 83 82

* U.S. Pharmacopeia, Vol. 16, p. 1072

** TJ.S. Hiarmacopela, Vol, 16, p. 1073

The emergency activities would take place after 8 hours, however the further observed clearance values showed that in the end the entire; Drug has been released.

In other words, the release of the drug was essentially the same in all three media that were observed during the trial period, although these "media" were largely different due to their chemical composition and pH value (water Bteutrält Miagensaft highly acidic and slightly alkaline llntestinaifltissigkeit), addition takes place di4 f reifebe - in, all Päll ^ i allniählich and at the same

distributed over the feeaate

, i i * ■ '- ■■■ ■ .. "' ■■ ■ '-: ■■

gat unansprtlohe 209814/1103

Claims (6)

Claims 1. A process for the production of medicaments in a dosage form suitable by staggered, timed release of the active ingredient, characterized in that dry, water- swellable pearls or spheres of a colloidal carrier substance in which the active ingredient is evenly distributed in encloses an envelope made of a plastic film that is permeable to water that diffuses through it, but is inert to gastrointestinal fluid, the carrier substance, the material for the film case and the beading of the film being coordinated with one another in such a way that when the colloidal substance swells, the envelope is under the influence of the penetrating water bursts as soon as the swelling pressure exceeds the cohesive force of the plastic film, 2. The method naoh spoke 1, characterized in that one is used as the colloidal carrier substance Gelatin used, which is preferably less than $ 11 Contains water. 3. The method according to claim 1 or 2, characterized in that one for the film shell ethyl cellulose, a chlorotrifluoroethylene or el »tetrafluoroethylene resin 209814/1583 or a yinyl chloride-tinylidene chloride copolymer is used. 4. The method according to any one of claims 1 to 3 »thereby characterized in that the plastic film is through Spray onto the beads or spheres in a vertical air stream brings up. 5. Dosage form suitable for internal administration for the timed or staggered release of medicinal products, thereby g e k en η ζ e rejects the remedy in a bead or globule from a swellable, colloidal carrier substance is finely divided, which included is anas in one of the body fluids inert, indigestible, but permeable to water shell Kunststoffilra, being the colloidal carrier substance that Material for the film envelope and the thickness of the latter are coordinated so that when swelling the colloid substance under the influence of the penetrating by diffusion Water bursts the film envelope as soon as the swelling pressure dip Exceeds the force of colysis of the film forming the envelope. 6. Drug dosage according to claim 5 »thereby g e k e η η ζ e i c h η et that the unit to be administered of a plurality of film-coated beads exists, in which the type and amount of the colloidal carrier substance and / or the thickness of the film coating are so adjusted '· 2098H / 1563 is that "in the case of the individual pearls the period of time up to is different for bursting, wherein the pearls, optionally within a common envelope, are arranged in this way that the release of the drug is timed. staggered bursting of the individual! "envelop continuously over a longer period of time, preferably over at least 8 to 12 hours. 8629 209 814/156