DE3400496A1 - DEVICE FOR DELIVERING AN ACTIVE SUBSTANCE BY OSMOSIS EFFECTIVE - Google Patents

Description

EUROPEAN PATENTATTORNEYS d.pu-chem. d _R. e.frf.herr von ρεοημλ

- O'DR.-ING. DIETER BEHRENS

LA-57 892 D-8000 MUNICH

λ ™ λι, r- ~ SCHWEIGERSTRASSE 2

Note: Alζa Corp.

phone: (089) 66 20 51 telegram: protectpatent TELEX: 524070

description Device effective through osmosis for the delivery of an active

fabric

The invention relates to a new and inexpensive osmotic delivery device for delivering an active ingredient an environment (drug dispenser). In particular concerns the invention a device with a wall consisting of a semipermeable component and an enteric component or enteric component for controlling the rate of release of the active ingredient from the device to the environment

Osmotic drug delivery devices with controlled delivery patterns can be and with longer delivery times are z. Known from U.S. Patents 3,845,770 and 3,916,899. The dispensing devices described there consist of a semipermeable wall that surrounds a chamber in which the active ingredient is contained. The semi-permeable wall is permeable for the passage of an external liquid, but impermeable to the passage of the active ingredient and has an opening for the release of the active ingredient Substance from the device.

/ 2

U.S. Patents 4,036,227, 4,093,708, 4,096,238, 4,135,514 and 4,142,526 is an improvement in osmotic delivery devices in U.S. Patents 3,845,770 and 3,916,899. The improvement is that a enteral, d. H. intestinal layer is provided, which does not dissolve or does not disintegrate in the stomach, but only in the intestine and which is applied to the outside of the semipermeable wall of the dispensing device. The ο dispensing device, which is completely covered with the enteric layer, only sets the active ingredient in the intestine and not yet free in the stomach.

The above-mentioned delivery devices represent a tremendous improvement in the field of osmotic delivery devices and are useful for delivering a myriad of drugs to the environment in which they are used. It has now been found that the device can be unexpectedly improved, which leads to even better results. For example, it will be recognized by those skilled in the art of drug delivery that if a new and effective delivery device were provided, in the device is used ₍ a significant clinical advantage would arise and a significant contribution to the field of active ingredient release.

It is therefore the object of the invention _; to develop a new osmotic delivery device for releasing an active ingredient to achieve a specific effect, which has advantages over the known laminated devices. The device is designed to self-control its permeability in response to changes in the liquid environment.

/ 3

- £ ■

This object is achieved by the device characterized in more detail in the main claim. Advantageous configurations this device are specified in the subclaims.

In the accompanying drawings

Fig. 1 is a view of an osmotic therapeutically effective Dispensing device suitable for the oral (ingestion and) delivery of a drug FIG. 2 is a view of the osmotic therapeutic delivery device of FIG. 1 taken along Li

is never cut open 2-2 to reveal the inside of the device

3a shows a diagram (delivery profile) of an osmotic delivery device, which shows the rate of release in an acidic environment against time,

3b shows a graphic representation of the total amount dispensed (cumulative amount) in an acidic environment for an osmotic device according to the invention, FIG. 4a a graphical representation of the delivery rate in an alkaline environment for an invention

proper osmotic delivery device and

Figure 4b shows the total amount delivered by an osmotic delivery device is released in an alkaline environment.

In the accompanying figures, which show examples of osmotic delivery devices according to the invention, in FIG FIGS. 1 and 2 show one embodiment of an osmotic delivery device, designated 10. the Device 10 comprises a body 11 with a wall 12 which surrounds an inner chamber, as can be seen from FIG. A passage 13 in the wall 12 connects the interior of the osmotic Dispensing device 10 with the exterior of the device 1 0.

/ 4

- έ-

In Figure 2, the osmotic delivery device 10 is the pig. I. shown in cutaway form with a portion of the wall 12 cut open and turned outwardly around the internal structure of the osmotic delivery device 10 to show. The device 10 comprises a composite wall consisting of a semi-permeable polymer and a enteric agent, the wall being the inner chamber

14 surrounds and forms. The wall 12 of the device 10 is made Made of a semi-permeable polymer that allows the passage of an external liquid that is in the environment of the application present is permeable and for the passage of the drug and other compounds present in the chamber 14 or compounds present in the environment of use are substantially impermeable, as well as an enteric one Agent which is substantially insoluble in gastric fluid and substantially insoluble in intestinal fluid is soluble. The wall 12 consists of a combination of the semi-permeable and enteric materials that are not toxic.

The chamber 14 contains a drug, which is indicated by points

15 and which is preferably soluble in the external liquid which penetrates into the chamber 14 and creates an osmotic pressure gradient across the wall 12 with respect to the external fluid. With another Embodiment, the drug 15 has a limited Solubility in the external liquid which enters the chamber 14 and is mixed with an osmotically effective one Compound 16 which is indicated by dashes and which is soluble in the liquid and has an osmotic Pressure gradient across the wall 12 with respect to the outer Generated liquid. Chamber 14 optionally contains a non-toxic dye to identify the

/ 5

-sr-

Drug 15 and to make the release of drug 15 visible to the naked eye.

The osmotic delivery device 10 releases the active ingredient 15 contained in the chamber 14 in the stomach area by drawing liquid into the chamber 14 to establish an osmotic equilibrium at a rate controlled by the permeability of the composite semipermeable-enteric wall 12 and the osmotic pressure gradient across the wall 12 _(in order to continuously release the active ingredient 15, the active ingredient 15 being released from the device 10 through the passage 13 at a controlled continuous rate over a longer period of time. That is, in the stomach, liquid penetrates through the semipermeable polymer into the Chamber and forms a solution containing the drug that is delivered from the device to the stomach over time.

The osmotic delivery device 10 places the in the chamber 14 contained active ingredient 15 over the above for the stomach area described mechanism in the intestine free and additionally in that the enteric agent from the Wall 12 is detached or leached, whereby the permeability of the wall 12 is increased and consequently the continuous rate of release of the active ingredient 15 to the intestine is controlled.

The osmotic delivery device 10 delivers the active ingredient 15, which has a limited solubility in the liquid and is mixed with an osmotically active compound is free in that liquid is sucked through the wall 12 into the chamber 14 in the stomach or intestinal region

/ 6

establish osmotic equilibrium at a rate which is controlled by the permeability of the wall 12 and the osmotic pressure gradient across the Wall 12 in order to continuously release the osmotically active connection in the chamber 14. This creates a Solution containing the active ingredient 15 and from the device 10 via the outlet opening 13 with controlled and continuous speed is delivered over a longer period of time.

The osmotic delivery device 10 of FIGS. 1 and 2.

can be in many embodiments including the preferred Embodiments for oral use are made. The oral system is adapted to the gastrointestinal tract either a local or a systemic drug over a long period of time submit. The osmotic oral therapeutic delivery device 10 can take several conventional shapes and sizes to have. It can be round with a diameter of 3.175 to 14.287 cm or it can be capsular in shape Orally administrable sizes range from 000 to 0 and from 1 to 8, etc.

In FIGS. 3a and 3b, the rate of release of an active ingredient versus time and the total amount (cumulative Amount) of active ingredient delivered versus time for an osmotic delivery device and release indicated in an acidic environment such as gastric fluid. In Figures 4a and 4b, the dispensing speed is opposite the time and the total amount of active ingredient released versus time for an alkaline environment as it is present in the intestinal fluid in the intestinal area of the gastrointestinal tract.

/ 7

-3-

While Figures 1 and 2 are exemplary of various osmotic delivery devices 10 that are made in accordance with the invention These dispensers can be made very different shapes and sizes Assume sizes and be suitable in their mode of action for the delivery of different drugs or active ingredients to different biological hosts and biological environments.

To achieve the objects, features and advantages of the invention, ös has been found that an osmotic delivery device for release of a drug to the gastrointestinal tract, including the stomach and intestines _y can be produced according to the invention. The osmotic abs-

T5 dispensing device includes a wall surrounding a chamber and educates. The chamber contains an active ingredient or a medicament and optionally an osmotically active one soluble substance. In the wall there is a passage for the delivery of the active substance from the device.

The wall of the osmotic delivery device is formed from a composite material consisting essentially of made from materials that do not adversely affect the active ingredient, compound, or biological environment.

5 The wall is composed of a selectively permeable polymeric material and an enteric material that are homogeneously or heterogeneously mixed with one another or within one another are dispersed to form an intimate mixture to produce an osmotically effective wall.

As selectively permeable polymers suitable for making the semipermeable wall of the osmotic delivery device For example, members of the group come into consideration: cellulose acylate, cellulose diacylate, cellulose

/8th

■ / If ·

triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, Alkyl cellulose, ethyl cellulose, polyamides Polyurethanes, and the like, suitable semipermeable polymers for making osmotic delivery devices are indicated U.S. Patents 3,845,770, 3,916,899, 4,008,719, 4,036,228, and 4,111,210.

The enteric materials associated with the semipermeable Polymers that can be used to make the wall of the delivery device are non-toxic enteral or enteric substances. These substances and their breakdown products should be physiologically inactive and the enteric materials should be off during the time the delivery device remains in the stomach Do not dissolve or disintegrate in the stomach and they should dissolve or disintegrate once the delivery device is used enters the intestine. The enteric materials useful in the present invention include those Materials that can be broken down or digested by enzymes in the intestinal tract, enteric materials, which contain an ionizable polyacid, preferably a long-chain polymer with ionizable carboxyl groups and the like. Typical enteric materials include keratin, keratin sandarac tolu balsam, salol, salol with β-naphthyl benzoate and Acetotannin, Salol with Peru balsam, Salol with Tolu balsam, Salol with MastMiarz Salol and Stearic acid, salol and shellac, formalinized gelatin, formalinized cross-linked gelatine and exchange resins, fatty acids, fats, waxes, fatty acid-wax mixtures, Myristic acid / hydrogenated castor oil / cholesterol, stearic acid / sheep ta] g, stearic acid / tolu balsam, stearic acid / castor oil, shellac, shellac treated with ammonia, shellac treated with ammonia / salol, shellac / Wool fat, shellac / cetyl alcohol, shellac / stearic acid

/ 9

Tolu balsam, shellac / n-butyl stearate, abietic acid, methylabietate, Benzoin, tolu balsam, sandarac, mastic with tolu balsam, mastic with cetyl alcohol, cellulose acetate phthalate, Cklliuoseaoetat -phthalat with resinous carrier, cellulose acetate and shellac, starch acetate phthalate, polyvinyl acid phthalate, acid methyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, 2-ethoxy-5- (2-hydroxyethoxymethyl-cellulose-phthalic acid, acid phthalates of carbohydrates, zein, alkyl resin / unsaturated fatty acid / shellac, hippuric acid, ternary copolymers of styrene, Copolymers of methacrylic acid and methyl methacrylate such as methacrylic acid / methacrylate 50:50 and methacrylic acid / methyl methacrylate copolymer 30:70, hydrolyzed styrene / maleic anhydride / copolymer, poly (methyl vinyl ether maleic anhydride), carboxylated copolymer of vinyl acetate, colophonium, £ 3 = mix of zein and carboxymethyl cellulose, acid methyl cellulose phthalate, styrene / maleic acid monoester copolymer, Styrene / maleic acid / maleic acid monoesterpolymers, Partial ester of isopropyl poly (vinyl methyl ether / dialeinic anhydride) , Half-ester of poly (ethylene / maleic anhydride), half-ester of poly (vinyl methyl ether / maleic acid anhydride), Precipitation, association and polyelectrolyte polymers such as polyacrylic acid mixed with Polyvinylpyrrolidone, polyacrylic acid with polyethylene oxide, methyl vinyl ether / maleic anhydride with polyvinylpyrrolidone, Calcium chloride with poly (acrylamide), aluminum sulfate with polyacrylamide, amino acids with an isoelectric Point below pH 7 such as alanine, aspartic acid, cystine, glutamic acid, glycine, isoleucine, methionine, phenylalanine, Proline, sarconine, serine, threonine, tryptophene, tyrosine, valine and the like. The amount of enteric material that is present with mixed with the semipermeable polymer is approximately 0.5 to 40% by weight. Typical enteric materials are

/ 10

discussed in Remington's Pharmaceutical Sciences, 3rd ed. p 604-605, 1965, published in ack _M Publishing Co., Eaton, Penna., and in Biopharmaceutics and Relevant Pharmacokinetics, 1st ed. S .. 158-165, 1971 , published by Drug Intelligence Publications, Hamilton, Illinois.

The term "passage" as used herein includes an opening, a hole, a hole or the like through the wall. The term also includes a degradable one Element in the wall such as a gelatin stopper that is broken down in the area around the application and thereby creates a Forms passage. A detailed description of osmotic passages and the maximum and minimum dimensions such passages are given in U.S. Patents 3,845 and 3,916,899.

Plasticizers can optionally be included in the preparation for the wall _; to give it flexibility and to facilitate the dissolution and subsequent leaching of the enteric components. Such plasticizers are, inter alia, triethyl citrate, tributyl citrate, tributyrin, butylphthalyl butyl glycolate, triacetin, triethyl citrate, polyethylene glycol, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, corn oil, acetic acid tri-2-ethylhexyl citrate oil, acetic acid tri-2-ethylhexyl citrate oil, glycerine oil, cotton citrate oil, sorbitol oil, acetic acid tri-2-ethylhexyl citrate and the like

The term "active ingredient" as used herein means generally any compound, an agent or a mass, an active substance preparation or a mixture thereof, that is released from the delivery device (drug dispenser) can be to achieve a beneficial effect. The term medicinal product specifically includes any substance

'/ II-

which can have a local or systemic effect in (mammals) animals, birds, fish and reptiles. The term animal includes primates, humans, warm-blooded animals, sport and farm animals, dogs, cats, laboratory animals u. Ä. Inorganic comprise the active compounds or drugs that will be issued according to the invention and organic drugs such as central nervous system acting substances _(hypnotics (Sleeping pills), sedatives, psychological stimulants, tranquilizers, antisteroids, laxatives (laxatives), antidepressants, anti-seizure drugs, muscle relaxants, anti-Parkinson drugs, anesthetics, anti-inflammatory drugs, anti-malarial drugs, hormones, sympathomimetics, antibiotics, diuretics, anti-inflammatory drugs , Hypoglycemics, nutrients and the like. Examples of special drugs are aminobarbital, aminophylline, aminosalicylic acid, ammonium biphosphate, ammonium chloride, amylase, anti-histamine, aspirin, atropine sulfate, Avazyme, Choledyl, Chymoral, Chymoral-100, Chymotrypsin Sodium Diason, Diethylstilb estrol, e-mycin, ery-tab, erythromycin, ephedrine hydrochloride, iron-II-sulphate, gentian-violet, hemicellulase, hydralazine, hyoscine-hydrobromide, hyoscyamine-sulphate, hotycin, lipase, methenamine-mandelate, orenzym, ox bile- Extract, oxtriphylline, pancreatin, papain, phenobarbital, potassium chloride, potassium iodide, potassium thiocyanate, quinidine sulfate, rp-mycine, robimycin, sodium aminobenzoate, sodium biphosphate, sodium chloride, sodium salicylate, sodium secobarbital, stilboestrol, stilbetine, sulfalazine. The amount of active ingredient present in the delivery device will vary depending on the activity and the amount of drug being administered. Generally, the osmotic delivery device contains 0.05 to 3 grams or more, with individual delivery devices

/ 12

• V **> «<4w *

for example 5, 25, 50, 125, 250, 500 mg, etc. may contain. The active ingredient can be in the delivery device in various forms such as dispersion, granulate, powder, compressed mass, film and others. are present. The appropriate ones Active ingredients and the doses in which they are administered are known and z. B. stated in Pharmaceuticals Sciences von Remington, 15th ed., 1975, published by Mack Publishing Co., Easton, PA; The Drug, The Nurse, The Patient. Including Current Drug Handbook, 1974-1976 by Falconer st al, published by Saunder Company, Philadelphia, PA; in Physician Desk Reference, 33rd ed., 1979, published by Medical Economics, Oradell, NJ, in Ann. of Allergy, Vol. 41, pages 75-77, 1979; in medic. Forsch., Vol. 25, pp 1629 to 1935, 1975 and in J. Inter. Med. Res., Vol. 7, pp. 335-338, 1979.

The term "osmotically active compound", as used here, includes inorganic and organic compounds, which represent effective dissolved or soluble substances that over an osmotic pressure gradient create the wall of the dispenser against an external liquid. The osmotically soluble substances are favorably applied by homogeneous or heterogeneous mixing of a soluble substance with the active ingredient in the chamber of the dispenser. When used, these soluble substances osmotically draw fluid into the Dispensing device and form a solution of the soluble substance, which by osmotic action from the device is released and thereby transported dissolved and undissolved active ingredient. Osmotic soluble substances include compounds such as magnesium sulfate, magnesium chloride, Sodium chloride ^, lithium chloride, potassium sulfate, sodium sulfate, potassium chloride, potassium acid, mannitol, Urea, inositol, magnesium succinate, raffinose, sucrose, glucose and the like. The osmotically active soluble substance lies

/ 13

preferably in excess initially and it may be in any suitable physical form such as as particles, crystals, pellets, grains and the like. The amount of osmotically soluble material in the delivery device is about 0.5 to 500 mg or more.

The osmotically effective delivery device according to the invention can be manufactured according to standard processes. In one embodiment, for example, the medicament is _{mixed with other ingredients in a ball mill /} by calendering, stirring or the like and pressed into a preselected shape. The materials forming the wall are also mixed into a mass and applied to the compressed active substance core by dipping, molding or spraying. One method for applying the wall material is the air suspension technique. This method can be used to make a wall as described in U.S. Patent 2,799,341, in J. Am. Pharm. Assoc, Vol. 48, pp. 451-459, 1959 and in J. Am. Pharm. Assoc, Vol. 49, pp. 82-84, 1960.

The solvents used to make the wall include water, ketones, esters, ethers, alcohols, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatics, heterocyclic solvents and their mixtures. Typical solvents are acetone, diacetone, methanol, ethanol, isopropyl alcohol, Methyl isobutyl ketone, n-heptane, methylene dichloride, Ethylene dichloride, mixtures such as acetone with water, ethanol with water, acetone with ethyl alcohol, methylene dichloride with methanol, ethylene dichloride with methanol and the like

The invention is illustrated in more detail by the following example.

example

An osmotically effective delivery device for delivering the active ingredient hydralazine hydrochloride was as follows Manufactured: An active ingredient formulation for the chamber of the dispensing device was manufactured by Manufacturing of active ingredient cores weighing 275 mg, consisting of the active ingredient in an amount of 18.2% by weight Hydralazine hydrochloride, 75.9% by weight mannitol, 2.9% by weight hydroxypropyl methylcellulose and 3% by weight stearic acid. These ingredients were mixed to form a homogeneous mass and a core forming the chamber shape was produced by pressing the mass in a 9.5 mm (3/8 inch) standard concave punch in a manesty press with a Stamp pressure of 1.5 t.

The active ingredient core was then introduced into a vortex coating device and coated with a semipermeable-enteric mass - consisting of 35% by weight cellulose acetate with an acetyl content of 39.8%, 35% by weight cellulose acetate with an acetyl content of 32.0% and an enteric agent consisting of 15% by weight hydroxypropyl methylcellulose phthalate, grade 50 _/ and 15% by weight triacetin coated. This hasse was applied in the form of a solution of 5% by weight solids in a solvent system consisting essentially of 1900 g of methylene chloride and 1900 g of methanol. The dispensers were coated mg up to a wall weight of about 19 and dried in an air oven at 50 ⁰ C. A 254 µm (10 mil) opening was drilled through the wall with a laser beam to complete the manufacture of the osmotic delivery device.

/ 15

In Figure 3a, the delivery from the device is in gastric fluid shown at an average rate of approximately 0.5 mg / h. The measured The delivery rate of this device increases, as indicated in Fig. 4a, when it comes into intestinal fluid 6 times, d. H. about 3 mg / h too. The total amount released (of the active ingredient) in the gastric fluid is in Fig. 3b indicated and the total amount released (of the active ingredient) in the intestinal fluid is indicated in Fig. 4b.

The same systems as the one described above, but with a non-enteric caplet consisting of 15% by weight of hydroxypropyl methylcellulose, type 606, and 15% by weight of polyethylene glycol 4000, type 4000 instead of the enteric agent coated in the cellulose acetate wall, release the active ingredient at the same rate in the intestinal fluid as in aer gastric fluid.

6238

' AZ-

- blank page -

Claims (10)

EUROPEAN PATENTATTORNEYS d.pl.-chem. dr. e.fre.herr von pechman DR.-ING. DIETER BEHRENS O / Γ \ Γ \ / QC DIPL.-ING .; DIPL.-TPIRTSCH.-ING. RUPERT GO lnr-, QOO D-8000 MUNICH SCHWEIGERSTRASSE 2 Note: Alza Corp. phone: (089) 66 20 ji TELEGRAM: PROTECTPATENT TELEX: 524070 patent claims 1. Osmosis-effective device for dispensing a Active ingredient at a controlled rate to the gastrointestinal tract, comprising a) a shaped wall of a mass consisting essentially of a semipermeable material which surrounds and forms b) a chamber containing an active substance preparation which is soluble in the external fluid that enters the chamber and has an osmotic pressure gradient across the wall opposite the external fluid created when the delivery device is in the gastrointestinal tract is located and c) a passageway in the wall communicating with the chamber and the exterior of the dispenser 5 and through which the active ingredient preparation from the device can be delivered over a longer period of time, characterized in that the wall a contains an enteric (enteric) material 0 2. Device according to claim 1, characterized in that the active ingredient preparation is a dose unit contains the active ingredient. / 2 3. Apparatus according to claim 1 or 2, characterized in that the active ingredient preparation comprises an osmotically active solute. 4. Apparatus according to claim 1 to 3, characterized in that the wall is constructed so that it controls the permeability to the fluids of the gastrointestinal tract itself. 5. Apparatus according to claim 1 to 4, characterized in that the semipermeable material maintains its physical and chemical integrity in the gastrointestinal tract. 6. Apparatus according to claim 1 to 5, characterized in that • indicates that the enteric material dissolves in the intestine. 7. Apparatus according to claim 1 to 6, characterized in that - indicates that the enteric material is released from the wall in the intestine. 8. Apparatus according to claim 1 to 7, characterized in that the enteric material disintegrates in the intestine. 9. Apparatus according to claim 1 to 8, characterized in that the enteric material changes due to the alkaline environment of the intestine. 10. The device according to claim 1 to 9, characterized in that it has such a shape which is suitable for oral use. 6238