JPS60185711A - Osmotic pressure device and method of transmmiting useful drug thereby - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a device for osmotic pressure delivery. More specifically,
The present invention provides useful agents for the preparation of (1) controlled pulse (pu)
lse) rate at a constant rate followed by (11) at a substantially constant rate interrupted between pulses of increasing amounts of the beneficial agent; or (and) with increasing amounts of terminal pulse delivery
The present invention relates to a hyperosmotic device that delivers a terminal pulse followed by a substantially zero order delivery period from the osmotic device.

It has become a certain product. This osmotic pressure delivery device has wide applications in the pharmaceutical, veterinary, agricultural, and other industries. The osmotic devices used in these applications exhibit a substantially constant rate of beneficial agent delivery once a thermodynamic steady state is established by the device.

If the thermodynamic amount of beneficial agent could be maintained substantially constant in these nine device ports, a steady state would be established and the rate of drug delivery from the device would be constant over time. .

This is referred to as zero order delivery, a term proposed by physico-chemical rate researchers.
ase).

The osmotic devices described above are a significant advance in the zero-order delivery device industry for continuous and controlled rate dispensing of useful drugs. It has been unexpectedly discovered that pulsed administration of drug delivery provides therapeutic results. For example, low pulse doses of estradiol suppress gonadotropin secretion, whereas high pulse doses suppress the ovulatory surge of gonadotropin secretion.
) to stimulate Dragesu, Volume 26, 207-22
Reported on page 6 in 1982. The most effective therapeutic drug that can be used in this way is methylprednisolone pulse treatment for collagen and progressive glomerulonephritis;
Pulse administration of cyclophosphamide-pincristin-adriamycin in patients suffering from neuroblastoma; Pulse therapy of rifamubicin in Hansen's disease Artificial induction of labor with pulse administration of nioxidocin; Pulse administration of insulin for prevention of hyperglycemia etc., Ferti
l.

and 5teri1. Volume 59, pages 695-699,
1985: Vutr, Boles, Volume 21, 65
-74 pages, 198256, 184-191, 1981
and Diabetes, Volume 26, 57.1-58.
Reported on page 1, 1977.

Until now, there has been no device in the prior art that delivers useful drugs at pulse rates, combined with zero-order rate delivery. Therefore, as in the example mentioned above, for those skilled in the pharmaceutical industry, (a) 1;! (b) can be interrupted by pulsed delivery of drug (C
a) terminal pulse delivery of the drug; or (d) terminal pulse delivery capable of substantially constant delivery from the osmotic device;
It will be readily appreciated that there is a critical need to exist for a delivery device that is capable of delivering useful drugs at substantially zero order rates. Furthermore, such devices are novel and useful devices capable of delivering drugs at constant and pulse rates, and such devices are of obvious value and make a valuable contribution to the pharmacy industry. will also be recognized by those skilled in the art.

OBJECTS OF THE INVENTION Accordingly, in view of the foregoing description, it is an object of the present invention to provide a new and useful device capable of delivering a useful drug at a controlled rate with pulsed delivery of increasing amounts of the drug over a period of time. is the direct object of the present invention.

Another object of the present invention is that when thermodynamic conditions are established that allow pulsed delivery of a useful drug in an osmotic delivery device,
It is an object of the present invention to provide an osmotic delivery device capable of delivering useful pharmaceutical products at a controlled rate with timed pulse delivery.

Yet another object of the present invention is to deliver the drug at a controlled rate at a constant concentration for a fixed period of time, accompanied by pulsed delivery of the drug to achieve optimal efficacy of the drug.
It is an object of the present invention to enable the use of an osmotic pressure device to achieve maximum therapeutic effect, and to provide a more effective pharmaceutical treatment method.

Yet another object of the present invention is to administer drug concentrations within an effective therapeutic range for the minimum period of time necessary for treatment, followed by delivery of the drug by pulsed administration as required for definitive therapeutic treatment. Is there any medicine that can be used? An object of the present invention is to provide a high-pressure delivery device.

Yet another object of the present invention is to provide an osmotic delivery device that administers a useful drug at a pulse rate followed by delivery of a useful drug at a substantially zero order rate over an extended period of time.

Yet another object of the present invention is a device for osmotic pressure delivery with a dosing regime that includes constant delivery of the drug product with a number of pulses of delivery of the drug, and a method for dispensing drugs as a complete pharmaceutical therapy for humans. The purpose of the present invention is to provide a device which can be used for multiple purposes, and which requires manual intervention only at the beginning and, if desired, at the end of the treatment.

Yet another object of the present invention is to provide a device for dispensing a useful drug from an osmotic device having a terminal pulsed delivery followed by a period of substantially zero-order rate delivery. That's true.

Yet another object of the present invention is to provide an apparatus during zero-order rate delivery to deliver increased amounts of medication to patients who require additional medication at specific times during the day or during the day to maintain sustained therapeutic efficacy. It is an object of the present invention to provide a winter pressure delivery device characterized by zero-order rate drug delivery capable of delayed drug delivery in a larger amount than the amount delivered by the patient.

Another object of the present invention is to provide a method for pulsed administration of a useful drug to increase the degree of absorption from the dosage form at the end of treatment while providing zero-order rate delivery of the drug.

Other objects, features and advantages of the invention will become apparent to those skilled in the pharmaceutical arts from reading the specification of the invention in conjunction with the claims.

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the unexpected discovery that a osmotic delivery device having an adjusted delivery rate profile is available. The present invention provides an osmotic system that delivers a useful agent at a substantially zero-order rate for a period of time adjusted to time-dependent pulsed delivery of an amount of the useful agent that is greater than the zero-order rate delivered from an osmotic device. A pressure device is provided. Zero-order figure delivery is modulated by the zero-order figure being modulated by a pulse delivery that precedes this zero-order delivery, or by a pulse delivery that interrupts the zero-order, or by causing a modulated pulse at the terminal of the zero-order delivery. or by moving to a zero-order delivery following the terminal pulse. This unique delivery rate is achieved by loading the osmotic device with useful drugs and modulating agents. The regulator is the first of the two drugs to fall below saturation within the osmotic device. When this occurs, the dissemination of the beneficial agent increases and the delivery of the beneficial agent increases accordingly, providing a pulsed delivery for the device.

The useful drug and modulating agent are delivered by a osmotic device that is manufactured as an osmotic device. The osmotic device is located in the compartment (C
ompa'rtment). This compartment contains the pharmaceutical ingredients used for dosage unit dosage and delivery control. A passageway in the wall communicates the compartment with the exterior of the osmotic device for delivery of useful agents from the osmotic device.

The walls of the osmotic device are formed from a semipermeable composition that does not adversely affect the useful drug, modulating agent, and environment of use. The wall is formed of a semipermeable composition that is permeable to external fluids such as water and biological fluids, but impermeable to beneficial agents, modulators, and other components present within the compartment.

Selectively permeable polymers useful for making this permeation device include cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates,
Cellulose diacylate, cellulose triacylate,
It is represented by a member selected from the group consisting essentially of cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate globionate, and cellulose acetate butyrate.

Suitable semipermeable polymers useful in the manufacture of osmotic devices include U.S. Pat.
．． No. 899, No. 4,008,719, No. 4,05
No. 6,228 and No. 4,111,210. These patents are assigned to ALZA, Inc. of Valo Alto, California, the assignee of this patent application.

- In an embodiment, the wall of the osmotic device is a laminate with a semipermeable membrane in a layered assembly with a microporous membrane. A semipermeable membrane is formed from the polymer described above. The microporous membrane includes a plurality of micropores and interconnecting microchannels for entry of external fluid into the osmotic device. Microporous thin membranes, in addition to the aforementioned polymers, also contain biological
A pore-forming agent (formar) enclosure is included that dissolves or leaches from the membrane when the osmotic device is used in an iterogenic environment. Pore-forming agents are inert; they do not react with the material forming the microporous film.

Removal of the pore-forming agent results in fluid-filled passageways that cooperate with the semipermeable membrane to mediate fluid entry into the osmotic device. Typical pore formers are
These are sodium chloride, potassium chloride, sorbitol, mannitol polyethylene glycol, hydroxypropyl methylcellulose and hydroxypropyl methylcellulose. An osmotic dispensing device with a laminated wall of semipermeable membranes and microporous membranes is disclosed in U.S. Pat. No. 4,160,452, assigned to Alza Corporation. Other embodiments of the osmotic device have an outer surface coated with a dye-containing coating. This coating is water-resistant, water-bathable, and contains dyes that are water-resistant. This coating can be applied over semi-permeable wall mud or laminated membranes. For example, the coating may consist of hydroxypropyl methylcellulose mixed with a lake dye that is recognized as a drug under the Food, Drug, and Cosmetic Act.

The term passageway as used herein for an osmotic device includes a mouth, orifice, lumen, hole, etc. having an osmotic dimension through a wall. This expression also includes erodible elements in the membrane, such as gelatin plugs, which erodibly form osmotic passageways during environmental use.

A detailed description of the permeability passages and their maximum and minimum dimensions is disclosed in US Pat. No. 5.845.770 and US Pat. No. 6.916,899.

These patents have been assigned to Alde.

Compartment N of the osmotic device contains a non-equilibrium ratio of beneficial drug and regulator. Prior to the present invention, this compartment contained, for example, a useful drug and a leaching agent in a ratio that indicated mutual solubility between the components of the compartment.

In the present invention, the useful drug and modulating agent are present in non-equilibrium ratios. A moderator, optionally acting as a suppressor called an insolubilizer of the useful drug, is initially used with sufficient capping to make it the first of the two drugs to drop below saturation. This thermodynamic result concomitantly increases the solubility of the useful drug, thereby increasing the amount of useful drug delivered at the instant of the pulse.

The solubility of useful agents is reduced when co-dissolved with modulators. More particularly, this process occurs due to the presence of fluid entering the compartment through the semi-permeable membrane, whereby the modifier reduces the solubility of the useful drug in the presence of the incoming fluid.

In simultaneous solubilization of the acoustic tract, the useful drug and the i# permeability drug are present in equilibrium ratios, and the delivery rate distribution is as shown in Figures 1a and 1.
Shows traditional shapes as seen in Figure b. In Figures 1a and 1b, the delivery profiles of the useful agent in line a and the modulating agent in line are both linear for a period of time, and then both a and b are present in the liquid in the compartment. It decreases as the concentration decreases below saturation. In the present invention, co-solubilization of the useful drug and modulator is typically performed in a non-equilibrium ratio;
The delivery rate distribution is shown in Figures 2a and 2b.

In FIG. 2a, the concentration of regulator A is below the equilibrium ratio in the compartment, so that the useful agent A is depleted sooner than it is used up. As a result, the solubility of useful drug a increases rapidly in subsaturated moderator solutions, and the delivery rate of useful drug actually increases as seen in Figure 2b.

As the concentration of regulator decreases further, the 6a and 6b
There will be a pair of delivery velocity distributions as shown in the figure. Figure g5a shows the diagram as the concentration of regulator is decreased and Figure 6b shows the delayed delivery of the useful agent that occurs as the concentration of regulator decreases once. From the foregoing, the present invention provides an osmotic device for programming desired times for delivery, delayed delivery, and delayed pulsed delivery of useful drugs, all of which can be achieved by adjusting the concentration of modulating agent within the osmotic device. It becomes clear that methods are provided.

The timing of pulsing of the drug is a function of the modulator's strength and the properties of the osmotic system. The timing to begin pulse delivery is determined by the following formula: where T is the time to begin pulse delivery; Mo is the weight of modulating agent initially present in the osmotic device; h is is the thickness of the semipermeable wall; St is the total solubility of the modulating agent and beneficial agent within the osmotic device; p is the density of the total cap within the osmotic device; SO is The mutual solubility of the modulating agent in the aqueous medium is: Δ■ is the total osmotic pressure developed by both the modulating agent and the beneficial agent in the osmotic device; A is the total surface area of the compressed mass present in the compartment of the osmotic device).

Agents referred to herein as useful agents include: gravel killers, air purifiers, antioxidants, biocides, catalysts, chemical reactants, cosmetics, pharmaceuticals, disinfectants, fungicides, fermentants, Foods, food supplements, anti-fertility agents, fertilization promoters, fungicides, herbicides, insecticides, microbial attenuators
ator), nutrients, insecticides, plant growth promoters, plant growth inhibitors, preservatives, contraceptives, sterilizers, vitamins and other agents useful for environmental uses.

In this specification and the appended claims, pharmaceutical products (
The term drug includes any physiologically or pharmacologically active substance that has a local or systemic effect on animals, including warm-blooded animals, mammals, humans, primates, birds, reptiles and fish. It will be done.

The word animal also includes domestic animals, sheep, goats, cats, cows,
Includes sporadic and livestock and medicine and research animals such as horses and pigs, jungle animals and zoo animals. Active drugs include, without limitation, inorganic and organic compounds, hypnotics, sedatives, psychostimulants, tranquilizers, stimulants, anticonvulsants, muscle relaxants, antiparkinsonians, analgesics, anti-inflammatory agents. agents, anesthetics, muscle contracting agents, anti-infective agents, bactericidal agents, anti-malarial agents, hormonal agents, sympathomimetic agents, agents for correcting metabolic abnormalities, urine agents, anthelmintic agents, neoplastic agents, hypoglycemic agents, Includes products that act on the central nervous system, such as nutritional supplements, fats, eye drops, laxatives, stimulants, and diagnostic agents. The above drugs affect peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscle, cardiovascular, smooth muscle, blood circulation threads, synanocytes, neuroeffector junction sites, endocrine and hormonal systems, biological hypersensitivity reactions. system, reproductive system, skeletal system, local hormonal system, digestive system, excretory system, local hormonal and histamine suppressive system and central nervous system.

The amount of useful agent present in an osmotic device is generally a unit dosage amount to provide the desired therapeutic effect. This osmotic device can generally accommodate 0.05 ng to 5y or more, e.g. 25ng, i, 5 da, 501 n
9.1oo1ng, 12.51n9.250~. 500
7507/l&, 1.51, etc. are included.

Modifiers useful for purposes of the present invention include ionizable compounds, compounds that are polar in nature, inorganic acids, organic acids, bases, and salts that contain ions common to aqueous and biological fluids such as salts and drugs. It is soluble. In a preferred embodiment,
The aforementioned compounds are solids and dissolve in the fluid entering the osmotic device to form a solution. Examples of inorganic salts include lithium chloride, lithium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, potassium sulfate, potassium hydrogen chloride, sodium chloride, sodium sulfate, sodium sulfite, sodium nitrate, sodium nitrite, etc. A member chosen from a group consisting of

The organic acid salt is essentially a member selected from the group consisting of sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate, and the like. Therapeutically acceptable salts that have ions in common with useful drugs are sodium chloride and sodium indomethacin; triflupromacine hydrochloride and sodium chloride; or fetruzine seric acid and sodium sulfate. Ionizable solid acids useful as modifiers include from the group consisting essentially of tartaric acid, citric acid, maleic acid, malic acid, fumaric acid, tartronic acid, itaconic acid, adipic acid, conolilic acid, mesaconic acid, etc. expressed by a member who is exposed. The basic compound is coated with a member selected from the group consisting essentially of potassium carbonate, sodium carbonate, ammonium carbonate, and the like.

During periods of non-zero order velocity from the osmotic device, the concentration of regulator within the osmotic device is given by Equation 1.

Zo y, + −(t, −12,) (1) 3° (where CO is the concentration of the regulator in the osmotic pressure device during the non-zero period; t is the osmotic pressure is the total internal volume of the device; Zo is the zero-order delivery rate of the regulator; So is the solubility of the regulator; t is the time at the start of delivery; t2 is the zero-order delivery rate of the regulator. FIG. 4a shows the delivery rate diagram of the preparation N1) of Equation 1, which is the delivery time.

In contrast, the solubility of a useful drug is determined by the modulator once C
o approaches 0, and as CO decreases from 0 to Also, the regulator once C.

When is equal to the saturation concentration SO of the W4 moderator, once Ccl of the useful drug will be equal to once S'd of the mutual solubility of the useful drug and the modulator, i.e. Cd = S 0d. , which is shown in Figure 4b. Table 1 shows various types of N? Figure 2 shows experimental data for the solubility of the useful drug zaptamol in l + sodium chloride.

The vA degree of the useful agent decreases monotonically between these two limits once the moderator is exhausted and used up.

The useful drug delivery rate from an it 4-pressure device is given by Equation 2.

(dm/d t ) where d is the delivery rate of the useful drug; is the water permeability of the semipermeable dust; A is the base area of the osmotic device: h is the thickness of the semipermeable group; Cd is the degree of useful agent in the permeable device; π
t is the osmotic pressure generated by the combination of the beneficial agent and modulator).

As Co decreases continuously according to Equation 1, Cd increases from a small value S'd to a large value S'd.
vdt) is the delivery rate of the modulating agent. In this osmotic device, the total driving force for drug delivery is the product of πtCd. π
, cd is maximum at one time of the regulator. In the example shown in Table 1, the pulse peak is approximately C○/So:,
It's happening in 58.

Therefore, the modulator: useful drug ratio, R, is 'i So/Sd
0<R<(
So/Sd) is an arbitrary value.

Useful drugs and modifiers can be present in the compartment in combination with binders, dyes, lubricants, dispersants and pharmaceutical ingredients. Pharmaceutical formulation ingredients include binders such as poly(ethylene glycol), gelatin, gelatin, carboxycellulose, poly(vinyl alcohol) and poly(vinylpyrrolidone). Typical lubricants include stearic acid, magnesium stearate, zinc stearate, aluminium stearate, lodenated vegetable oils, and talc. The compartment may contain a disintegrant to form a bath of drug and regulator useful to facilitate controlled delivery from the osmotic device. Typical disintegrants include lightly crosslinked poly(vinylpyrrolidone), cornstarch, potato starch, Veegum, bentonite, and citrus pulp. Color retardants include non-containing additives such as Blue/161 in Lactose, which is approved under the Food, Drug and Cosmetic Act.

Depending on one's preference, the dye in the compartment and the Song Dynasty in the walls may be the same or different. The amount of binder, lubricant or disintegrant is usually about 0, oi, respectively, of the total weight present in the compartment.
% to 20%.

The inventive osmotic devices containing useful drugs, modulators, and other ingredients can be manufactured by standard manufacturing methods. For example, in embodiments, the useful agent is mixed with the modifier and other compartment core components in non-equilibrium ratios, and the components are rolled into a sphere and the final permeation pressure is reduced by rolling, stirring, and pressing. Create the planned shape according to the shape of the device. The material forming the walls of the device can be applied to the pressurized formulation by impregnation, molding or spraying. One method of applying semipermeable or laminated walls is the air suspension process.
dure). This method can form single-layer walls or laminated walls consisting of two layers. The air suspension method is described in U.S. Pat. No. 2,799,241, J. Am. P.
arm.

As5oc, Vol. 48, pp. 451-459, 1959 and the same magazine, Vol. 49, pp. 82-84, 1960. 4 Permeable passages can be made by mechanical drilling, laser drilling, and die punching or cutting. The path formation method using laser is
U.S. Patent No. 5.9, both assigned to Alde, Inc.
No. 16,899 and No. 4,088,864. Osmotic delivery devices designed for oral administration are circular or triple 0-0 and 1-8 in diameter from 3/16 inch to 9/16 inch.
It can also be in the form of a solid capsule with a range of dimensions. These shapes render the osmotic device suitable in size and configuration for administering drugs useful to warm-blooded animals, including humans. Other standard methods of manufacturing devices can be found in Modern Plastics Encyclopedia, Vol. 46, pp. 62-70, 1969;
Remington Pharmaceutical Science No. 14
edition, pp. 1649-1696: and Lacman (Lac
kman) et al., page 1.970.

The following examples are detailed illustrations of the invention and should not be construed as limiting the scope of the invention in any way; Further information will become clear to those skilled in the pharmaceutical arts upon reference to the appended claims.

Example 1 β delivered at constant rate adjusted by pulse rate
- salbutamol, an adrenergic stimulant and bronchodilator, i.e. α-
[(t-butylamino)methyl-4-hydroxy-m
An osmotic therapy device for the controlled delivery of xylene-alpha,alpha'-diol-hemisulfate is fabricated as follows: first, salbutamol hemisulfate (hereinafter referred to as salbutamol) is combined with the modifier sodium chloride. The solubility was measured in distilled water at 67°C and showed the following solubility: Solubility of salcitamol in water 2
751n9/1nt1 Solubility of salbutamol in a saturated solution of sodium chloride 16 mg/d, Solubility of sodium chloride in water 6211n9/-, Solubility of sodium chloride in a saturated solution of salbutamol 520 m1
/lnl, and the total solubility of salbutamol in saturated sodium chloride and the solubility of sodium chloride in water is 16+620=556 da/-.

A composition containing salcitamol:sodium chloride in a ratio of 1:5 was then prepared as follows:
1 Da salbutamol 72.301 N9 sodium chloride, 1.81 R9 cross-linked carboxymethyl cellulose and 1.8 to 1.8 poly(vinylpyrrolidone) were passed through a 60 mesh screen and mixed for 1 hour in pre-greasing. The blended ingredients were then transferred to a larger blender and granulation fluid 8-, consisting of 90:10 ethanol:water, was added thereto and all ingredients were blended for approximately 20 minutes. The homogeneously blended ingredients were passed through a 20 mesh screen and dried in a forced air oven at 50° C. for 12 hours. After drying, the granules were mixed with 0.9~ magnesium stearate and blended for 10 minutes.

The granules were transferred to a conventional manesty tablet press and compressed in a standard circular 5/32 inch die to a hardness of 1.5-2 kp. The area of this compressed drug core is 0.41 cIn” and 91.6~
The weight was .

This compressed core is coated with an Aeromatic■ air suspension coater.
) and a wall of cellulose acetate with an acetyl content was wrapped around the core. This semi-permeable wall is 59.
42.5% (12,'75) with 8% acetyl content
g) Cellulose acetate, co-solvent consisting of methylene chloride-methanol 80%-20% (588+++/
! -256-) in a composition containing 15% (4.5 g) of hydroxypropyl methylcellulose. After forming a wall around the ressrvoir, they were transferred into a forced air oven and dried at 50° C. for 48 hours. A permeable pressure passage 0.25 mm in diameter was then lasered through the semipermeable wall. The weight of this semi-permeable wall was 5.9 In9.

The useful drug osmotic pressure delivery device prepared in this example is shown in FIGS. 5 and 6. FIG. 5 shows an osmotic device consisting of a body 11 having a passageway 12 communicating the interior and exterior of the osmotic device 10. As shown in FIG. FIG. 6 shows a cutaway cross-section at 13 of device 10, including semipermeable wall 14 surrounding and defining interior compartment 15. FIG. Compartment 15 contains the active agent salbutamol 16, the regulator sodium chloride 17 and other pharmaceutical ingredients. FIG. 7 shows a delivery rate profile consisting essentially of a 7 hour zero order rate delivery conditioned by a 7 to 9 hour pulsed delivery of beneficial agent. 8th
The figure shows the cumulative amount of the beneficial drug salbutamol delivered over a 12 hour period. The bars in Figures 7 and 8 indicate the maximum and minimum amounts of delivery during the measurement.

``One row'' - salbutamol and the bronchodilator terbutaline sulfate at a constant rate interrupted by pulse rate delivery (
terbutalin 5ulbate), 1-(
An oral osmotic device for controlled four-hour delivery of 5°5-dihydroxyphenyl)-2-(t-butylamino)ethanol was constructed as follows: first 9.64 to 5 mg of salbutamol, 5 mg of Terbutaline sulfate, 24 ~ sodium chloride, 0.71 ~ poly(vinylpyrrolidone) and 0.71 m9 cross-linked carboxymethylcellulose were blended and passed through a 60 mesh screen.

The ratio of salbutamol:sodium chloride in the composition is 1:6.

Next, a granulated liquid consisting of 90:10 ethanol:water is added to the sieved blend, reducing the total ingredients to about 1
Blend for 5-20 minutes. Pass the well-blended ingredients through a 60 mesh screen and heat in a forced air oven at 50°C.
and dried for 12 to 15 hours. After drying, the granules were
651n9 stearic acid and blended for 10 minutes. This blend was then compressed into a drug formulation in precompartment form.

The compressed drug formulation was placed in an air suspension device and coated with the microporous film forming composition. This microporous film-forming composition consisted of 49% by weight of cellulose acetate with an acetyl content of 69.8%, 28.5% by weight of hydroxypropylmethylcellulose, and 22.5% by weight of polyethylene glycol 4000. The film was prepared using methylene chloride-ethanol (95%) film solvent (80:2
0 weight mold weight). This microporous thin film has a thickness of 0.12 feathers.

An outer semipermeable membrane was then laminated onto the microporous membrane in a conventional air suspension apparatus. This composition for forming a semipermeable membrane consisted of 90% by weight of cellulose acetate having an acetyl content of 69.8% and 10% by weight of cellulose acetate having an acetyl content of 62%. The semipermeable membrane was applied to the laminated structure using a solvent mixture consisting of methylene chloride and ethanol (80:20 weight type). Dry the osmotic device and use a radar to reduce the diameter to 0.26 mm! A passageway for J was opened through the laminated wall. FIG. 9 shows body 11, passageway 12, open cross section 13, outer semipermeable wall 14, inner compartment 15, salcitamol 16, sodium chloride 17, inner microporous wall 18 and terbutaline 19.

Example 6 Salt is -oxprenolol-H
An oral osmotic device for controlled continuous delivery of regulated salts dilenolol was fabricated by the general method previously described. In the osmotic pressure device of this example, the compartment contains 1 part ofsdilenolol hydrochloride and 6 parts potassium chloride:sodium chloride (50 parts
:50) in a non-equilibrium formulation. This compartment also contains 2 mg dextrose, 2 mg potato starch, and 5 rng magnesium stearate. This formulation after compression has a diameter of 9 tnm. This device has a laminated wall consisting essentially of 60% by weight of cellulose acetate with an acetyl content of 46.5% and a degree of substitution of 6 and 40% of cellulose acetate with an acetyl content of 69.8% and a degree of substitution of 2.4.

This semipermeable membrane is made of methylene chloride and methanol 80
:20! It is applied using a solvent consisting essentially of the following proportions: The device has an external microporous membrane consisting essentially of 55% by weight cellulose acetate with an acetyl content of 69.8% and also 65% by weight Nrbitol and 10% by weight polyethylene glycol 400. The film was prepared using a solvent consisting of methylene chloride-methanol in a 90:10 weight ratio. This semipermeable thin film has a thickness of 0.12
The thickness of the microporous thin film is 0.16 mm.

This device has a 0.25 mN passage.

Example 4 In this example, the salcitamol:sodium chloride ratio is 1 nia, and the permeable compartment contains 9.6 tm of salbutamol sulfate, 56 mg of sodium chloride, and 1.4 db of sodium chloride.
y poly(vinylpyrrolidone), 1.4119 cross-linked sodium carboxymethyl cellulose and 0.
The method of Example 1 is repeated to prepare a permeable pressure mold containing a drug formulation consisting essentially of 6 m9 of magnesium stearate. This device delivers salbutamol for 12 hours and has a terminal pulse delivery of salbutamol as shown in FIG. The permeable pressure mold was made of Example 10 semipermeable wall composition with a thickness of 4.9 mils (0,13111
10 with semi-permeable walls.

Example 5 A permeable pressure mold is made by the method of Example 1 with a salbutamol:modulator sodium chloride ratio of 1:9.

This permeable compartment contains 28.91n9 salbutamol sulfate, 216mg sodium chloride, 5.2~
poly(vinylpyrrolidone), 5.21n cross-linked sodium carboxymethyl cellulose and 2.67
A pharmaceutical formulation consisting essentially of 119 magnesium stearate is included. The permeable pressure mold has a 20.11n9 volume semipermeable wall containing the composition of Example 1. This device has 16 hours of zero-rate delivery of salbutamol followed by 8 hours of incremental salbutamol delivery. A 24-hour delivery diagram of this permeable pressure device is shown in FIG.

Example 6 Acebutotol for gastrointestinal administration
ol) An oral osmotic device for α-β-adrenergic blocking agent is manufactured with the following dimensions and configuration: 10 parts acebutotol hydrochloride and 90 parts potassium carbonate, 8.7
5+w non-crosslinked poly(vinylpyrrolido-') wo?
Pass through a 60 mesh stainless steel screen and blend for 1 hour at room temperature. Next, transfer the blended ingredients to a large blender and mix 90 parts of ethanol:water.
Add 40 g of granulation liquid, consisting of a 10 volume ratio, to the blender and blend the ingredients for 20 minutes. The fully blended ingredients are passed through a 60 mesh screen and dried in a forced air oven at 50°C for 16-17 hours.

Next, the dried granules were passed through a 20 mesh screen.
Add 5■ red sea bream sium stearate. This l
Blend the ingredients for 15 minutes and transfer the blended granules to a conventional Manestee press.

The ingredients are compressed into an acebutotol storage body approximately 6 mm in diameter.

The acebutotol precompartment-forming composition described above is transferred to an air suspension coater and surrounded by a semipermeable wall. The semipermeable wall is made of cellulose acetate 55 with an acetyl content of 69.8%.
g and essentially 550- ethylene chloride and 110 m
7! It is formed from a wall-forming composition containing an organic solvent consisting of methanol and methanol.

After forming a semipermeable wall around the drug reservoir, it is deep-dried in a forced air oven at 50° C. for 50 hours.

A 3.4 mm passageway is then laser drilled through the semi-permeable wall for communication between the exterior of the permeable pressure mold and the interior of the compartment straw.

The semi-permeable wall has an M content of 8.6 kg and the device delivers 12 hours of drug regulated by terminal pulse delivery.

Example 7 The method of Example 1 was repeated to produce an osmotic device, and a device was fabricated in which the useful drug salbutamol:modulator ratio was 1=9 and pulse delivery occurred near the middle of the delivery pattern. In Example 7, the permeable pressure-loading contained 9.6% by weight salbutamol, 169% by weight as the half-value salt, 85.8% by weight sodium chloride, 2% by weight cross-linked sodium carboxymethyl cellulose, 2% by weight of polyvinylpyrrolidone and 1% by weight of magnesium stearate. The apparatus consisted of 42.5 watts of cellulose in vinegar with 69.8% acetyl content, 42.5% by weight of cellulose acetate with 62% acetyl content, and 15% by weight of hydroxypropyl methyl cellulose. There is a gender barrier. The passageway diameter is 0.25-mm, the semipermeable wall thickness is 4.8 mg, and the wall thickness is 0.06 mm. The delivery pattern measured by this osmotic pressure device is shown in FIG. 12, and the cumulative delivery is shown in FIG. 16.

Presently preferred embodiments of the invention are: (A) (a)
A wall formed of a non-toxic, semi-permeable composition that allows the passage of external fluids but is substantially impermeable to the passage of pharmaceutical agents and modulating agents that the wall surrounds and forms. ) a compartment containing a dosage unit amount of the drug and an effective amount of the modulating agent that serves to deliver the drug in pulses; and (C) external to the osmotic device and internal to the osmotic device. (B) an oral osmotic device shaped and dimensioned for the patient's gastrointestinal tract, including a passageway in the wall for communicating with the patient's gastrointestinal tract; (C) receiving an external fluid entering the compartment through the semipermeable membrane at a determined rate to form a solution containing a pharmaceutical agent that is hydraulically and by osmotic pressure delivered from the osmotic device; delivery of a therapeutically effective amount of a drug at a substantially constant rate with pulsed delivery of an effective amount of drug greater than a fixed amount into the gastrointestinal tract of a patient over an extended period of time; is a method of constant rate delivery of medicines regulated by pulsed delivery of medicines, which consists in obtaining the desired effect of medicine administration by means of pulsed delivery.

This osmotic device is an implant.
Alternatively, a conduit may be connected to the passage for intravenous administration of pharmaceuticals or subcutaneous administration of pharmaceuticals. Medicinal products delivered at zero-order rates with pulse rates include: controlled, substantially constant delivery methods of salbutamol with pulse delivery of salbutamol; controlled, substantially constant delivery methods of acebutolol with time-dependent pulse delivery of acebutolol Fixed delivery method: Includes a method of treating asthma that provides a beneficial effect to a patient suffering from asthma by administering to the patient a therapeutically effective amount of salbutomol in fixed doses punctuated by pulse rate doses of salbutomol. Salbutamol and acebutolol are also administered in a manner that causes bronchodilation in patients requiring bronchial dilators, particularly for acute and chronic patients. 1 above
The drug is delivered at a controlled continuous rate over a period of 15 minutes to 24 hours with intermediate pulses or terminal pulses delivered from 15 minutes to 24 hours.

The present invention provides an osmotic therapy device manufactured in the form of an osmotic device for creating improved drug delivery programs. While novel features of the invention have been described and pointed out as presently preferred embodiments, those skilled in the art will recognize that various modifications, changes and omissions of the invention as illustrated and described can be made without departing from the spirit of the invention. It will be recognized.

[Brief explanation of the drawing]

Figures 1a and 1b are delivery rate diagrams for the normal co-solubilization case where the beneficial agent and regulator are present in equilibrium ratios within the compartment, with the beneficial agent at line a and the regulator at line a. It's a line. Figures 2a and 2b are delivery rate diagrams for simultaneous solubilization where the beneficial agent and modulator are present in non-equilibrium ratios;
? Is IMb a regulator? fsa is a useful drug. FIG. 6a is a diagram of the modulator delivery rate as the concentration of the modifier decreases. FIG. 6b is a delayed delivery rate diagram of beneficial agent with one decrease in modulator. FIG. 4a is a delivery pattern for the regulator of Formula 1. FIG. 4b is a diagram showing the relationship between the useful drug concentration Cd and the regulator concentration CO when Cd;S' d becomes a small value. FIG. 5 shows the osmotic pressure device 10 manufactured according to Example 1. FIG. 6 is an open cross-sectional view at 13 of the osmotic device 10. Figure 87 is a 7-hour zero-order delivery pattern adjusted by a 7- to 9-hour pulse delivery by the device described above. FIG. 8 is a diagram showing cumulative transmission over 12 hours. FIG. 9 is a sectional view of the osmotic pressure device 10 of the second embodiment. FIG. 10 is a delivery diagram with pulse delivery at the end. FIG. 11 shows a 24-hour transmission pattern. FIG. 12 is a measured delivery pattern of the osmotic pressure device according to Example 7. FIG. 16 is a cumulative delivery diagram of wax measured by the osmotic pressure device according to Example 7. Agent Ko Asamura 1S FIG, lo FIG, l+ Continued from page 1 @ Inventor Felix S. Amenis Runrika 1643 Four Leaf Lane, Los Altos, California, United States Procedural amendment (voluntary) January 21, 1985 To the Commissioner of the Patent Office 1. Indication of the case Patent Application No. 253946 of 1982 2. Title of the invention Osmotic pressure device and method for delivering beneficial drugs using the same 3. Person making the amendment Relationship to the case Patent applicant address Name and address Corporation (name) 4. Agent ko 5. Date of amendment order ii J 1920, 1.1 h. and line 18, “4C
The figure shows a pulse when Cd increases from 50d (small value to Sd (large value)) with the continuous decrease of co, and the value according to equation 2 becomes large.

Claims (1)

[Claims] (t) (a) Permeable to the passage of external fluids;
(b) having a wall formed of a semipermeable composition substantially impermeable to the passage of the beneficial agent, the nuclide serving to deliver the beneficial agent and the beneficial agent in pulses; a compartment containing a modulating agent; and (c) communicating the interior of the device with the exterior of the device through a separate wall, enclosing and forming a passageway for conveying said beneficial agent to the environment of use. An osmotic device for delivering a beneficial agent to the environment in which it is used, characterized in that: (2) a four-pressure device for delivering a beneficial agent to an environment of use as claimed in claim 1 in which substantially zero-order delivery of a beneficial agent occurs after said pulsed delivery of a beneficial agent; . (3) An osmotic pressure for delivering a beneficial agent to a use environment according to claim 1, wherein substantially zero-order delivery of a beneficial agent is interrupted by pulsed delivery of said beneficial agent. Device. 4. A perosmotic device for delivering a beneficial agent to an environment of use as claimed in claim 1, wherein the pulsed delivery of the beneficial agent occurs after substantially zero-order delivery of the beneficial agent. (51) A bath for delivering a beneficial agent to a use environment according to claim 1, wherein said pulsed delivery of said beneficial agent is in an amount substantially greater than the amount delivered in a zero-order delivery. (6) The ratio of the amount of regulating agent to the useful drug present in the osmotic device is 2〇<R< (S o/S d ), (wherein R is the ratio and SO is the mutual solubility of said modulating agent and Sd is the mutual solubility of said beneficial agent. (7) Beneficial to the environment of use according to claim 1, wherein the regulator is a member selected from the group consisting essentially of inorganic acids, inorganic acids, bases and salts. (8) A composition useful for dispensing salbutamol and chloride in pulsed rate delivery after substantially zero-order rate delivery from an osmotic delivery device. (9) The osmotic device for delivering a beneficial agent to a use environment according to claim 1, wherein the beneficial agent is a pharmaceutical. (10) ( a) having a wall formed of a non-toxic material that is permeable to the passage of external fluids but substantially impermeable to the passage of salbutamol and the moderator, and wherein the nuclide is (b) salbutamol; and Ui) agent (said regulator is present in an amount less than that required to maintain its saturation in the fluid entering the device, thereby controlling the fluid entering the device). (C) articulates with the exterior of the device through said wall to provide controlled delivery of salbutamol from the osmotic device; An osmotic device for the controlled delivery of sargetamol, characterized in that it surrounds and defines a passageway. α1) (a) (1) A wall formed of a 10-suitable polymeric composition permeable to the passage of external fluids but substantially impermeable to the passage of beneficial agents and modulating agents. , the walls of which have (11) a compartment containing the useful drug and the modulating agent (
(i) the modulating agent is one that effects the pulsatile release of the beneficial agent from the osmotic device; (b) displacing the semipermeable wall from the environment to introduce fluid into the pressure-controlled device; of the useful agent at a zero-order rate adjusted by the pulsed rate of delivery of the agent at a substantially zero-order rate adjusted by the pulsed rate of delivery of the drug through the passageway into the environment of use as a substantially zero-order rate delivery of the agent. Sending method.