CA1315200C - Sustained-release particulate preparation and process for preparing the same - Google Patents
Sustained-release particulate preparation and process for preparing the sameInfo
- Publication number
- CA1315200C CA1315200C CA000547960A CA547960A CA1315200C CA 1315200 C CA1315200 C CA 1315200C CA 000547960 A CA000547960 A CA 000547960A CA 547960 A CA547960 A CA 547960A CA 1315200 C CA1315200 C CA 1315200C
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- Prior art keywords
- solution
- sustained
- preparation
- molecular weight
- active agent
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Abstract
SUSTAINED-RELEASE PARTICULATE PREPARATION AND
PROCESS FOR PREPARING THE SAME
Abstract:
A sustained-release particulate preparation having a controlled releasing rate of a pharmacologically active agent contained therein in the living body, and a process for preparing the preparation are disclosed. The prepara-tion comprises a polymeric compound which is capable of being degraded in the living body and which is compatible with living tissue, a pharmacologically active agent, and a natural high molecular weight compound of sugar origin or a derivative thereof. The preparation has fine and uniform particle size and can be administered subcutaneously or intramuscularly for obtaining a long-lasting pharmacological activity.
PROCESS FOR PREPARING THE SAME
Abstract:
A sustained-release particulate preparation having a controlled releasing rate of a pharmacologically active agent contained therein in the living body, and a process for preparing the preparation are disclosed. The prepara-tion comprises a polymeric compound which is capable of being degraded in the living body and which is compatible with living tissue, a pharmacologically active agent, and a natural high molecular weight compound of sugar origin or a derivative thereof. The preparation has fine and uniform particle size and can be administered subcutaneously or intramuscularly for obtaining a long-lasting pharmacological activity.
Description
`` -1- ~3~2~0 SUSTAINED-RELEASE PA~TICULATE PREPARATION AN~
PROCESS FOR PREPARING THE SA~E
Field of the Invention This invention relates to a sustained-release particulate preparation having a controlled releasing rate of a pharmacologically active agent in the living body, and a process for preparing such a sustained-release particulate preparation.
Background of the Invention Hitherto, an extensive research has been made for the stud~ of a sustained-release preparation for the purpose of controlling the releasing rate of a pharmaceutically active agent in the living body thereby obtaining a long-lasting pharmacological activity. For example, sustained-release particulate preparations, in the form o~ microspheres or microcapsules using a polymeric material such as polylactic acid, polyglycolic acid, etc~ which is capable of being decomposed in the living body and is compatible with liviny tissues, have been proposed.
However, the above conventional preparations have problems in that the production of fine particles having uniform particle size and shape is difficult, and loughness and heterogenity are sometimes ~ormed on the surface of the particles. Another problem of the conventional preparation is that the production of particles having substantially the same particle size with high reproducibility is very difficult.
The above problems associated with the conventional preparations bring about various disadvantages so that the control of the releasing rate of pharmacologically active agents contained therein, which is the most important re~uirement for the sustained-release preparation, sometimes becomes difficult. As a result, serious side-effects may be noted due to the rapid releasing rate of the active agent, particularly, when the dose level is increased for obtaining a long-lasting pharmacological effect of the active agent.
On the other hand, when the releasing rate ls too low, the desired pharmacological effect cannot be achieved thereby ~ .
" ~3~0~
adversely af~ecting the therapeutic effect on the disease to be treated with the sus~ained-release preparation.
The present inventors conducted extensive studies on the sustained-release preparations in order to overcome the above disadvantages of the conventional preparation, in particular, on the selection of polymeric compounds as a basic component which is capable of being degraded in the living body and which is compatible with living tissue, as well as the particle size of the preparation, and, as a result, found that certain types of polymeric compounds can be preferably used as a basic component of the sustained-release preparation. However, with respect to the particle size, it was found that the desired object cannot be achieved without any break-through since particles tend to be integrated or aggregated with each other during the formation of particles.
With respect to the particle size, Japanese Pharmacopea stipulates the maximum particle size of particles to be used in the injectable preparations. That is, in General Rules of Preparation, Item of Injection, it is stipulated that the particle sizes suspended in the preparation of suspension injectable preparations must be 150 ~m or less, and, hence, a particle size larger than 150 ~m cannot be used Eor the injectable preparations. For this reason, conventional particles used for suspension injectable preparations must be subjected to a fractionating operation using a sieve for regulating the particle size so as to meet the above regulation of the Japanese Pharmacopea.
Apparently, such an operation is time-consuming and expen-sive since it should be conducted under aseptic and dust-ree conditions, and, therefore, an improvement in the production of particulate preparations on an industrial scale has long been desired in the art.
Summary of the Invention As a result of further studies for establishing a process for preparing fine particulate preparations having a fine and uniform particle size and keeping chemical and physical stability without employing the fractionating 13~2~
operation for regulating the particle size, the presentinventors found that the desired object can be achieved by using a natural high molecular weight compound vf sugar origin or a derivative thereof as a medium for the particle formation, and completed the present invention based on the above finding.
~ hat is, the present invention relates to a sustained-release particulate preparation which comprises a polymeric compound which is capable of being degraded in the living body and is compatible with living tissue, a pharma-cologically active agent, and a natural high molecular weight compound of sugar origin or a derivative thereof, and a process for preparing the sustained-release particulate preparation.
An object of the present invention is therefore to provide a sustained-release particulate preparation contain-ing a pharmacologically active agent and having a fine and uniform particle size and keeping chemical and physical stability in an injectable formulation having a controlled releasing rate of the active agent.
Another object of the present invention is to provide - a process for preparing such a sustained-release particulate preparation which can be performed easily, without necessity of fractionating regulation of the particle size using a sieve.
Brief Description of the Drawinqs Figs. 1 and 2 are graphs showing changes in the level of peripheral neutrocytes in blood samples after subcutane-ous and intramuscular administrations of the s~stained-release particulate preparations containing G-CSF prepared in Examples 1 and 2 of the present invention and the aqueous solution of G-CSF as a control.
Detailed Description of the Invention The polymeric compound which is capable of being degraded in the living body and which is compatible with living tissue used as one oE the components of the sustained-release particulate preparation according to the present invention, is selected from the group consisting of ~L3~2a~
polylactic acid, polyglycolic acid, pol~hydroYybutyric acid and a copolymer thereof having a molecular weight of from about 1,000 to about 25,000. The polymeric compound can be used in an amount of from about 20 to about 95% by weight, preferably ~rom 40 to 90% by weight, based on the total wei~ht o~ the particulate preparation.
The pharmacologically (or physiologically) activ2 agents used in the preparation of the present invention can be any type of active agents which are desirably used as sustained-releasing in the living body, but are prefe-ably those which are water-insoluble or difficulty soluble in ater, since it is necessary that a solution of the active agent is suspended in an aqueous solution during the produc-tion of the particulate preparation.
Examples of suitable pharmacologically active agents include organic compounds such as ketoprofen, nicorandil, disopyramide, etc., proteins such as interferons, tumor necrosis factor (TNF), colony-stimulating factor, etc.
A suitable example of the colony-stimulating factor includes a granular colony stimulating factor (hereinafter referred to as "G-CSF") as disclosed in the Applicant's copending Canadian Patent Application Nos. 487,077 and 518,286 filed July 18, 1985 and September 16, 1986, respectively.
These pharmacologically active agents can be used in an amount of from about 0.01 to about 50~ by weight based on the total weight of the particulate preparation.
The medium which can be used for the formation of particles and which is one of the essential components of the preparation of this invention is a natural high molecular weight compound of sugar origin or a derivative thereof. Examples of such compounds include at least one member selected from chitins or derivatives thereof, chitosans or derivatives thereof, hyaluronic acid or a salt thereof such as sodium hyalurate, dextrans having a molecular weight of from a~out 10,000 to about 150,000, pectins, de~trins having a molecular ~eight of from about 2,500 to about 150,000, and chondroitin sulfate or a salt thereof such as sodium chondroitin sulfate.
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131~2~
The proportion of the rnedium can be varied suitably depending upon the type of the medium used and/or the dosage form oE the particulate preparation so as to provide the final preparation with a desired releasing rate of the active agent. For example, in order to adjust the particle size and surface smoothness of the particles for obtaining a suitable releasing rate, an aqueous solution of the medium having a concentration of from 0.1 to 20% by weight can be used in a proportion of 1 to 20 times (by volume) the solution of the above-described polymeric compound and the pharmacologically active agent.
The sustained-release particulate preparation accord-ing to the present invention can be prepared in the follow-ing manner.
(1) A polymeric compound ~hich is capable of b~ing decomposed in the living body and is compatible with living tissue is dissolved in an organic solvent.
(2) A pharmacologically active agent is added to the solution prepared in (1) above to form a solution, suspen-sion or emulsion.(3) An aqueous solution of a medium comprising a natural high molecular weight compound of sugar origin or a deriva-tive thereof is mixed with the solution (or suspension or emulsion) prepared in (2) above, followed by stirring to prepare fine particles containing the pharmacologically active agent.
(4) The fine particles obtained in (3) above are isolated from the mixture to obtain the desired sustained-release fine particulate preparation.
Examples of the organic solvents used above include methyl acetate, ethyl acetate, methyl alcohol, ethyl alcohol, isobutyl alcohol, n-propyl alcohol, isopropyl alcohol, acetone, methylene chloride, toluene, benzene and the like, either alone or as a mixture thereof~
In order to dissolve (or suspend or emulsify) the pharmacologically active agent in the solution of the polymeric compound, it is preferred to use a surEace active agent having an HLB (hydrophilic-lipophilic balance) of 8 or " ' ' ' - ' , :
.
~3~5200 less. Examples of the surface active agents having an HLB
of 8 or less incl~lde at le~st one of egg yolk lecithin, hydrogenated lecithin, aliphatic acid esters of sorbitan, aliphatic acid esters of polyoxyethylene and aliphatic acid esters of glycerin.
It is necessary that all the above process steps are conducted aseptically.
The sustained-release particulate preparation accord-ing to the present invention may contain additional compo-nents such as a dispersing agent, a preservative, a pain-alleviating agent, and the like.
The sustained-release particulate preparation accord-ing to the present invention can be administered through various routes depending upon the conditions of the disease to be treated, but, generally can be used by subcutaneous or intramuscular injection.
The present invention is further illustrated in more detail by the following examples and test example, but the present invention is not limited thereto. Unless otherwise indicated, all parts, percents, ratios and the like are by weight.
Example 1 A poly(dl-lactic acid-glycolic acid) copolymer (75:25) having a molecular weight of about 2,000 was dissolved in 200 ml of a mixture of methylene chloride and n-propanol (4:1 by volume) to prepare a 5~ solution of the copolymer. Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 50 ml of a mixture of methylene chloride and n~propanol (4:1 by volume) was added to the above-prepared methylene chloride-n-propanol solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer to prepare a mixed solution.
The resulting mixed solution was added to 1,000 ml of a 1~ aqueous solution of hyaluronic acid which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing G-CSF.
The microspheres were collected by centrifugation, repeated-ly washed 5 times with distilled water which had been kept ~3~52~
at 40C and then dried under reduced press~re at room temperature. The G-CSF microspheres obtained in this way was a write powder having an average particle size of 100 ~m or below. All the above steps for the preparation were conducted aseptically.
Example 2 A poly(dl-lactic acid-hydroxybutyric acid) copolymer (90:10) having a molecular weight of about 2,000 was dissolved in 200 ml of a mixture of toluene and methylene chloride (4:1 by volume) to prepare a 5% solution of the copolymer. Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 50 ml of a mixture of toluene and methylene chloride (4:1 by volume) was added to the above-prepared toluene-methylene chloride solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer to prepare a mixed solution.
The resulting mixed solution was added to 1,000 ml of a 0~ aqueous solution of chitin which had been kept at 40C, and the mixture was emulslfied while stirring at a rate of 500 rpm to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere prepara-tion as a white powder having an average particle size of lOQ ~m or less. All the above steps for the preparation were conducted aseptically.
Example 3 A poly(dl-lactic acid-hydroxybutyric acid) copolymer (90:10) having a molecular weight of about 2,000 was dissolved in 200 ml of methylene chloride to prepare a 5~
solution of the copolymer. Then, 50 mg of nicorandil was added to the above methylene chloride solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer.
The resulting mixed sol~tion was added to 1,000 ml of a 0.2% aqueous solution of hyaluronic acid which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing nicorandil. The resulting microspheres were worked up in .
.:
' ~ , , ' .
13~2~
the same manner as described in Example 1 to obtain a micro-sphere preparation as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 4 A poly-dl-lactic acid polymer having a molecular weight of about 2,000 was dissolved in 50 ml of a mixture of toluene and acetone (5:1 by volume) to prepare a 10~
solution of the polymer. Then, a suspension of 2.5 mg oE
freeze-dried G-CSF powder in 50 ml of 80% aqueous propanol was added to the above-prepared tolunene-acetone solution oE
the polymer, and the mixture was stirred and mixed while stirring at 1,000 rpm with a stirrer to prepare a mixed solution.
The mixed solution was then added to 500 ml of a 0.5%
aqueous chitosan solution which had been warmed at ~O~C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing G-CSF. The resulting microspheres were then worked up in the same manner as described in Example 1 to obtain a microspher~e preparation containing G-CSF as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 5 A poly-dl-lactic acid polymer having a molecular weight of about 20,000 was dissolved in 50 ml Gf benzene to prepare a 5% solution of the polymer, and egg yolk lecithin was added to the solution in an amount of 1% concentration.
Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 30 50 ml of 40~ aqueous propanol was added to the above-prepared benzene solution of the polymer, and the mixture was emulsified while stirring and mixing at a rate of 1,000 rpm with a stirrer.
The emulsified mixture was added to a 5~ aqueous 35 solution of dextran which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner 13~2~
g as described in Example 1 to obtain a microsphere prepara-tion containing G-CSF as a white powder having an average particle size of 100 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 6 A poly(dl-lactic acid-glycolic acid) copolymer (5Q:50) having a molecular weight of about 6,000 was dissolved in 50 ml of methylene chloride to prepare a 5~
solution of the copolymer, and 50 mg of disopyramide was added to the solution. Then, 500 ml of a 1% aqueous pectin solution which had been kept at 40C was added to the mix-ture, and the mixture was emulsified while stirring at a rate of 1,000 rpm with a stirrer. After stirring for 1 hour, methylene chloride was evaporated to produce micro-spheres containing disopyramide. The resulting microsphereswere worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing disopyramide as a white powder having an average particle size of 100 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 7 A poly(dl-lactic acid-glycolic acid) copolymer (80:20) having a molecular weight of about 2lO00 was dissolved in 50 ml of methylene chloride, and egg yolk lecithin was added to the solution in an amount of 1~
concentration. Then, a 40% aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentra-tion of 500 ~g/ml in 40% aqueous propanol was added to the above-prepared methylene chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of lrO00 rpm with a stirrer. The emulsi~ied mixture was added to 500 ml of a 1% aqueous pectin solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF. I'he resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing .: , ~ , .
' ~ 3~2~
G-CSF as a ~hite powder having an average particle size o~
100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 8 ~ poly-dl-lactic acid polymer having a molecular weight of about 4,000 was dissolved in 50 ml of a mixture of methylene chloride and ethanol to produce a 10~ solution of the polymer, and 2.5 mg of freeze-dried ~-interferon powder was added to the solution. Then, a 0.5% aqueous chitosan solution which had been warmed at 40C was added to the mixtl-re, and the mixture was emulsified while stirring at a rate of 1,000 rpm with a stirrer. After stirring for 1 hour, methylene chloride and ethanol were evaporated to produce microspheres containing a-interferon. The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing a-interferon as a white powder having an average particle size of 100 ~m or less. All the above steps for the prepa-ration were conducted aseptically.
Example 9 A poly(dl-lactic acid-glycolic acid) copolymer (50:50) having a molecular weight of about 6,000 was dissolved in 50 ml of methylene chloride to prepare a 5%
solution of the copolymer, and hydrogenated lecithin was added to the solution in an amount of 1% concentration.
Then, a 40~ aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentration of 500 ~g/ml in 40%
aqueous propanol was added to the above-prepared methylene 3~ chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of 1,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 1~ aqueous chitosan solution which had been warmed at 40C, and the mixture was emulsified while stirring at a 35 rate of 500 rpm to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere prepara-tion containing G CSF as a white powder having an average 13~!~2~
particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 10 A poly(glycolic acid-hydroxybutyric acid) copolymer (50:50) having an molecular weight of about 2,000 was dissolved in 50 ml of methylene chloride to prepare a 5%
solution of the copolymer, and hydrogenerated lecithin was added to the solution in an amount of 1% concentration.
Then, a 70% aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentration of 500 ~g/ml in aqueous propanol was added to the above-prepared methylene chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of l,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 1% aqueous sodium hyalurate solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF. The resulting mlcrospheres were worked up in the same manner as described in Example l to obtain a microsphere preparation containing G-CSF as a - white powder having an average particle size of lO0 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 11 A poly-dl-lactic acid polymer having a molecular weight of about 20,000 was dissolved in 50 ml of methylene chloride to prepare a 5% solution of the polymer, and egg yolk lecithin was added to the solution in an amount of l~
concentration. Then, a solution prepared by suspending 2.5 mg of a freeze-dried r-interferon powder in 50 ml of 40~
aqueous propanol was added to the above-prepared methylene chloride solution of the polymer, and the mixture was emulsified while stirring and mixing at a rate of l,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 5~ aqueous dextran solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres 13~2~
containing y-interferon. The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containin~ y-interferon as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Test Example 1 The effect of the sustained-release particulate preparation containing G-CSF prepared in Examples 1 and 2 above was tested using ~ister-Imamichi male rats (13 weeks-old). The test was conducted by withdrawing a blood sample for a control at 9 a.m. on the first day, and then admin-istering (1) a physiological saline solution which also contains 0.5% rat serum albumin and a 1% physiological saline solution of mannitol, (2) an aqueous solution of G-CSF as a control, or (3) the sustained-release particulate preparation of Example 1 or 2.
In this experiment, the test sample was administered subcutaneously or intramuscularly in the back-neck site of the rats according to the follo~ing schedule. That is, the physiological saline solution was administered in an amount of 0.5 ml/rat once a day for two weeks; the aqueous G-CSF
solution was administered in an amount of 0.5 ml/rat (2.5 ~g as G-CSF) once a day for two weeks; and each of the G-CSF-containing sustained-release particulate preparations obtained in Examples 1 and 2 was administered in an amount of 0.5 ml/rat (10 ~g as G-CSF) at a single dose, followed by evaluating the effect over a period of 2 weeks.
The evaluation of the effect was performed in terms of changes in the number of peripheral neutrocytes as compared with that of the aqueous G-CSF solution as a control. More specifically, an amount of erythrocytes, leukocytes and hemoglobin in the blosd sample withdrawn by ~uncture of the back medial branch of vein was determined using a microcell counter (Toa CC170 Model) and also the hemogram was obtained by a smear preparation of the blood sample. The number of neutrocytes was calculated as a 1 ~:L ~2~
product of the numbers of the leukocytes. The results obtained are shown in the accompanying drawings.
Figs. 1 and 2 illustrate graphs showing the amount of neutrocytes (x 102 cells/mm3 blood) over a period of two weeks obtained by administering the test sample. The graph "A" shows a result obtained by subcutaneous administration of the preparation of Example 1 (10 ~g G-CSF/rat/dose); the graph "B" shows the result obtained by intramuscular admin-istration of the preparation of Example 1 (10 ~g ~-CSF/
rat/~ose); the graph "C" shows the result obtained by subcutaneous administration of the preparation of Example 2 (10 ~g/rat/dose); the graph "D" shows the result obtained by subcutaneous administration of the physiological saline solution (0 ~g G-CSF/rat/day); and the graph "E" shows the result obtained by subcutaneous administration of the G-CSF
aqueous solution as a control (2.5 ~g/rat/day).
The results in Figs. 1 and 2 clearly demonstrate that the sustained-release particulate preparations according to the present invention exhibit the increase in the number of neutrocytes on every test day after administration to a degree which is substantially equivalent to or higher than that of the control.
As is apparent from the test results, the sustained-release particulate preparation according to the present invention is effective for preventing undesirable hydrolysis of physiologically active agents with enzymes after admin-istration which is often observed in usual injectable preparations, as well as for preventing polymerization of the active agent and the like. Further, the test results indicate that the sustained-release particulate preparation of this invention exhibits an effect substantially equiva-lent to or even higher than the effect obtained by the control at a lower dose level of the active agent than that of the control.
The sustained-release particulate preparation oE the present invention has a structure of microspheres or micro-capsules which can be used as an injection or a depo-type preparation, and is excellent in view of their uniformity in `` 13~2~
grain distribution, fineness of particles and surface smoothness of particles~ A~cordingly, the sustained-release particulate preparation of this invention is excepted to be useful for the treatment of various diseases since a constant blood level of the physiologically active agent can be maintained after administration of a single dose of the preparation and a long-lasting effect of the active agent can be obtained over a long period of time.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
PROCESS FOR PREPARING THE SA~E
Field of the Invention This invention relates to a sustained-release particulate preparation having a controlled releasing rate of a pharmacologically active agent in the living body, and a process for preparing such a sustained-release particulate preparation.
Background of the Invention Hitherto, an extensive research has been made for the stud~ of a sustained-release preparation for the purpose of controlling the releasing rate of a pharmaceutically active agent in the living body thereby obtaining a long-lasting pharmacological activity. For example, sustained-release particulate preparations, in the form o~ microspheres or microcapsules using a polymeric material such as polylactic acid, polyglycolic acid, etc~ which is capable of being decomposed in the living body and is compatible with liviny tissues, have been proposed.
However, the above conventional preparations have problems in that the production of fine particles having uniform particle size and shape is difficult, and loughness and heterogenity are sometimes ~ormed on the surface of the particles. Another problem of the conventional preparation is that the production of particles having substantially the same particle size with high reproducibility is very difficult.
The above problems associated with the conventional preparations bring about various disadvantages so that the control of the releasing rate of pharmacologically active agents contained therein, which is the most important re~uirement for the sustained-release preparation, sometimes becomes difficult. As a result, serious side-effects may be noted due to the rapid releasing rate of the active agent, particularly, when the dose level is increased for obtaining a long-lasting pharmacological effect of the active agent.
On the other hand, when the releasing rate ls too low, the desired pharmacological effect cannot be achieved thereby ~ .
" ~3~0~
adversely af~ecting the therapeutic effect on the disease to be treated with the sus~ained-release preparation.
The present inventors conducted extensive studies on the sustained-release preparations in order to overcome the above disadvantages of the conventional preparation, in particular, on the selection of polymeric compounds as a basic component which is capable of being degraded in the living body and which is compatible with living tissue, as well as the particle size of the preparation, and, as a result, found that certain types of polymeric compounds can be preferably used as a basic component of the sustained-release preparation. However, with respect to the particle size, it was found that the desired object cannot be achieved without any break-through since particles tend to be integrated or aggregated with each other during the formation of particles.
With respect to the particle size, Japanese Pharmacopea stipulates the maximum particle size of particles to be used in the injectable preparations. That is, in General Rules of Preparation, Item of Injection, it is stipulated that the particle sizes suspended in the preparation of suspension injectable preparations must be 150 ~m or less, and, hence, a particle size larger than 150 ~m cannot be used Eor the injectable preparations. For this reason, conventional particles used for suspension injectable preparations must be subjected to a fractionating operation using a sieve for regulating the particle size so as to meet the above regulation of the Japanese Pharmacopea.
Apparently, such an operation is time-consuming and expen-sive since it should be conducted under aseptic and dust-ree conditions, and, therefore, an improvement in the production of particulate preparations on an industrial scale has long been desired in the art.
Summary of the Invention As a result of further studies for establishing a process for preparing fine particulate preparations having a fine and uniform particle size and keeping chemical and physical stability without employing the fractionating 13~2~
operation for regulating the particle size, the presentinventors found that the desired object can be achieved by using a natural high molecular weight compound vf sugar origin or a derivative thereof as a medium for the particle formation, and completed the present invention based on the above finding.
~ hat is, the present invention relates to a sustained-release particulate preparation which comprises a polymeric compound which is capable of being degraded in the living body and is compatible with living tissue, a pharma-cologically active agent, and a natural high molecular weight compound of sugar origin or a derivative thereof, and a process for preparing the sustained-release particulate preparation.
An object of the present invention is therefore to provide a sustained-release particulate preparation contain-ing a pharmacologically active agent and having a fine and uniform particle size and keeping chemical and physical stability in an injectable formulation having a controlled releasing rate of the active agent.
Another object of the present invention is to provide - a process for preparing such a sustained-release particulate preparation which can be performed easily, without necessity of fractionating regulation of the particle size using a sieve.
Brief Description of the Drawinqs Figs. 1 and 2 are graphs showing changes in the level of peripheral neutrocytes in blood samples after subcutane-ous and intramuscular administrations of the s~stained-release particulate preparations containing G-CSF prepared in Examples 1 and 2 of the present invention and the aqueous solution of G-CSF as a control.
Detailed Description of the Invention The polymeric compound which is capable of being degraded in the living body and which is compatible with living tissue used as one oE the components of the sustained-release particulate preparation according to the present invention, is selected from the group consisting of ~L3~2a~
polylactic acid, polyglycolic acid, pol~hydroYybutyric acid and a copolymer thereof having a molecular weight of from about 1,000 to about 25,000. The polymeric compound can be used in an amount of from about 20 to about 95% by weight, preferably ~rom 40 to 90% by weight, based on the total wei~ht o~ the particulate preparation.
The pharmacologically (or physiologically) activ2 agents used in the preparation of the present invention can be any type of active agents which are desirably used as sustained-releasing in the living body, but are prefe-ably those which are water-insoluble or difficulty soluble in ater, since it is necessary that a solution of the active agent is suspended in an aqueous solution during the produc-tion of the particulate preparation.
Examples of suitable pharmacologically active agents include organic compounds such as ketoprofen, nicorandil, disopyramide, etc., proteins such as interferons, tumor necrosis factor (TNF), colony-stimulating factor, etc.
A suitable example of the colony-stimulating factor includes a granular colony stimulating factor (hereinafter referred to as "G-CSF") as disclosed in the Applicant's copending Canadian Patent Application Nos. 487,077 and 518,286 filed July 18, 1985 and September 16, 1986, respectively.
These pharmacologically active agents can be used in an amount of from about 0.01 to about 50~ by weight based on the total weight of the particulate preparation.
The medium which can be used for the formation of particles and which is one of the essential components of the preparation of this invention is a natural high molecular weight compound of sugar origin or a derivative thereof. Examples of such compounds include at least one member selected from chitins or derivatives thereof, chitosans or derivatives thereof, hyaluronic acid or a salt thereof such as sodium hyalurate, dextrans having a molecular weight of from a~out 10,000 to about 150,000, pectins, de~trins having a molecular ~eight of from about 2,500 to about 150,000, and chondroitin sulfate or a salt thereof such as sodium chondroitin sulfate.
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131~2~
The proportion of the rnedium can be varied suitably depending upon the type of the medium used and/or the dosage form oE the particulate preparation so as to provide the final preparation with a desired releasing rate of the active agent. For example, in order to adjust the particle size and surface smoothness of the particles for obtaining a suitable releasing rate, an aqueous solution of the medium having a concentration of from 0.1 to 20% by weight can be used in a proportion of 1 to 20 times (by volume) the solution of the above-described polymeric compound and the pharmacologically active agent.
The sustained-release particulate preparation accord-ing to the present invention can be prepared in the follow-ing manner.
(1) A polymeric compound ~hich is capable of b~ing decomposed in the living body and is compatible with living tissue is dissolved in an organic solvent.
(2) A pharmacologically active agent is added to the solution prepared in (1) above to form a solution, suspen-sion or emulsion.(3) An aqueous solution of a medium comprising a natural high molecular weight compound of sugar origin or a deriva-tive thereof is mixed with the solution (or suspension or emulsion) prepared in (2) above, followed by stirring to prepare fine particles containing the pharmacologically active agent.
(4) The fine particles obtained in (3) above are isolated from the mixture to obtain the desired sustained-release fine particulate preparation.
Examples of the organic solvents used above include methyl acetate, ethyl acetate, methyl alcohol, ethyl alcohol, isobutyl alcohol, n-propyl alcohol, isopropyl alcohol, acetone, methylene chloride, toluene, benzene and the like, either alone or as a mixture thereof~
In order to dissolve (or suspend or emulsify) the pharmacologically active agent in the solution of the polymeric compound, it is preferred to use a surEace active agent having an HLB (hydrophilic-lipophilic balance) of 8 or " ' ' ' - ' , :
.
~3~5200 less. Examples of the surface active agents having an HLB
of 8 or less incl~lde at le~st one of egg yolk lecithin, hydrogenated lecithin, aliphatic acid esters of sorbitan, aliphatic acid esters of polyoxyethylene and aliphatic acid esters of glycerin.
It is necessary that all the above process steps are conducted aseptically.
The sustained-release particulate preparation accord-ing to the present invention may contain additional compo-nents such as a dispersing agent, a preservative, a pain-alleviating agent, and the like.
The sustained-release particulate preparation accord-ing to the present invention can be administered through various routes depending upon the conditions of the disease to be treated, but, generally can be used by subcutaneous or intramuscular injection.
The present invention is further illustrated in more detail by the following examples and test example, but the present invention is not limited thereto. Unless otherwise indicated, all parts, percents, ratios and the like are by weight.
Example 1 A poly(dl-lactic acid-glycolic acid) copolymer (75:25) having a molecular weight of about 2,000 was dissolved in 200 ml of a mixture of methylene chloride and n-propanol (4:1 by volume) to prepare a 5~ solution of the copolymer. Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 50 ml of a mixture of methylene chloride and n~propanol (4:1 by volume) was added to the above-prepared methylene chloride-n-propanol solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer to prepare a mixed solution.
The resulting mixed solution was added to 1,000 ml of a 1~ aqueous solution of hyaluronic acid which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing G-CSF.
The microspheres were collected by centrifugation, repeated-ly washed 5 times with distilled water which had been kept ~3~52~
at 40C and then dried under reduced press~re at room temperature. The G-CSF microspheres obtained in this way was a write powder having an average particle size of 100 ~m or below. All the above steps for the preparation were conducted aseptically.
Example 2 A poly(dl-lactic acid-hydroxybutyric acid) copolymer (90:10) having a molecular weight of about 2,000 was dissolved in 200 ml of a mixture of toluene and methylene chloride (4:1 by volume) to prepare a 5% solution of the copolymer. Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 50 ml of a mixture of toluene and methylene chloride (4:1 by volume) was added to the above-prepared toluene-methylene chloride solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer to prepare a mixed solution.
The resulting mixed solution was added to 1,000 ml of a 0~ aqueous solution of chitin which had been kept at 40C, and the mixture was emulslfied while stirring at a rate of 500 rpm to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere prepara-tion as a white powder having an average particle size of lOQ ~m or less. All the above steps for the preparation were conducted aseptically.
Example 3 A poly(dl-lactic acid-hydroxybutyric acid) copolymer (90:10) having a molecular weight of about 2,000 was dissolved in 200 ml of methylene chloride to prepare a 5~
solution of the copolymer. Then, 50 mg of nicorandil was added to the above methylene chloride solution of the copolymer, and the mixture was stirred and mixed while rotating at a rate of 1,000 rpm with a stirrer.
The resulting mixed sol~tion was added to 1,000 ml of a 0.2% aqueous solution of hyaluronic acid which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing nicorandil. The resulting microspheres were worked up in .
.:
' ~ , , ' .
13~2~
the same manner as described in Example 1 to obtain a micro-sphere preparation as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 4 A poly-dl-lactic acid polymer having a molecular weight of about 2,000 was dissolved in 50 ml of a mixture of toluene and acetone (5:1 by volume) to prepare a 10~
solution of the polymer. Then, a suspension of 2.5 mg oE
freeze-dried G-CSF powder in 50 ml of 80% aqueous propanol was added to the above-prepared tolunene-acetone solution oE
the polymer, and the mixture was stirred and mixed while stirring at 1,000 rpm with a stirrer to prepare a mixed solution.
The mixed solution was then added to 500 ml of a 0.5%
aqueous chitosan solution which had been warmed at ~O~C, and the mixture was emulsified while stirring at a rate of 500 rpm to produce microspheres containing G-CSF. The resulting microspheres were then worked up in the same manner as described in Example 1 to obtain a microspher~e preparation containing G-CSF as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 5 A poly-dl-lactic acid polymer having a molecular weight of about 20,000 was dissolved in 50 ml Gf benzene to prepare a 5% solution of the polymer, and egg yolk lecithin was added to the solution in an amount of 1% concentration.
Then, a suspension of 2.5 mg of freeze-dried G-CSF powder in 30 50 ml of 40~ aqueous propanol was added to the above-prepared benzene solution of the polymer, and the mixture was emulsified while stirring and mixing at a rate of 1,000 rpm with a stirrer.
The emulsified mixture was added to a 5~ aqueous 35 solution of dextran which had been kept at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner 13~2~
g as described in Example 1 to obtain a microsphere prepara-tion containing G-CSF as a white powder having an average particle size of 100 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 6 A poly(dl-lactic acid-glycolic acid) copolymer (5Q:50) having a molecular weight of about 6,000 was dissolved in 50 ml of methylene chloride to prepare a 5~
solution of the copolymer, and 50 mg of disopyramide was added to the solution. Then, 500 ml of a 1% aqueous pectin solution which had been kept at 40C was added to the mix-ture, and the mixture was emulsified while stirring at a rate of 1,000 rpm with a stirrer. After stirring for 1 hour, methylene chloride was evaporated to produce micro-spheres containing disopyramide. The resulting microsphereswere worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing disopyramide as a white powder having an average particle size of 100 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 7 A poly(dl-lactic acid-glycolic acid) copolymer (80:20) having a molecular weight of about 2lO00 was dissolved in 50 ml of methylene chloride, and egg yolk lecithin was added to the solution in an amount of 1~
concentration. Then, a 40% aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentra-tion of 500 ~g/ml in 40% aqueous propanol was added to the above-prepared methylene chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of lrO00 rpm with a stirrer. The emulsi~ied mixture was added to 500 ml of a 1% aqueous pectin solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF. I'he resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing .: , ~ , .
' ~ 3~2~
G-CSF as a ~hite powder having an average particle size o~
100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 8 ~ poly-dl-lactic acid polymer having a molecular weight of about 4,000 was dissolved in 50 ml of a mixture of methylene chloride and ethanol to produce a 10~ solution of the polymer, and 2.5 mg of freeze-dried ~-interferon powder was added to the solution. Then, a 0.5% aqueous chitosan solution which had been warmed at 40C was added to the mixtl-re, and the mixture was emulsified while stirring at a rate of 1,000 rpm with a stirrer. After stirring for 1 hour, methylene chloride and ethanol were evaporated to produce microspheres containing a-interferon. The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containing a-interferon as a white powder having an average particle size of 100 ~m or less. All the above steps for the prepa-ration were conducted aseptically.
Example 9 A poly(dl-lactic acid-glycolic acid) copolymer (50:50) having a molecular weight of about 6,000 was dissolved in 50 ml of methylene chloride to prepare a 5%
solution of the copolymer, and hydrogenated lecithin was added to the solution in an amount of 1% concentration.
Then, a 40~ aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentration of 500 ~g/ml in 40%
aqueous propanol was added to the above-prepared methylene 3~ chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of 1,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 1~ aqueous chitosan solution which had been warmed at 40C, and the mixture was emulsified while stirring at a 35 rate of 500 rpm to produce microspheres containing G-CSF.
The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere prepara-tion containing G CSF as a white powder having an average 13~!~2~
particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Example 10 A poly(glycolic acid-hydroxybutyric acid) copolymer (50:50) having an molecular weight of about 2,000 was dissolved in 50 ml of methylene chloride to prepare a 5%
solution of the copolymer, and hydrogenerated lecithin was added to the solution in an amount of 1% concentration.
Then, a 70% aqueous propanol solution containing G-CSF at a concentration of 50 ~g/ml which was prepared by dissolving a G-CSF solution having a concentration of 500 ~g/ml in aqueous propanol was added to the above-prepared methylene chloride solution of the copolymer, and the mixture was emulsified while stirring and mixing at a rate of l,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 1% aqueous sodium hyalurate solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres containing G-CSF. The resulting mlcrospheres were worked up in the same manner as described in Example l to obtain a microsphere preparation containing G-CSF as a - white powder having an average particle size of lO0 ~m or less. A11 the above steps for the preparation were conducted aseptically.
Example 11 A poly-dl-lactic acid polymer having a molecular weight of about 20,000 was dissolved in 50 ml of methylene chloride to prepare a 5% solution of the polymer, and egg yolk lecithin was added to the solution in an amount of l~
concentration. Then, a solution prepared by suspending 2.5 mg of a freeze-dried r-interferon powder in 50 ml of 40~
aqueous propanol was added to the above-prepared methylene chloride solution of the polymer, and the mixture was emulsified while stirring and mixing at a rate of l,000 rpm with a stirrer. The emulsified mixture was added to 500 ml of a 5~ aqueous dextran solution which had been warmed at 40C, and the mixture was emulsified while stirring at a rate of 500 rpm with a stirrer to produce microspheres 13~2~
containing y-interferon. The resulting microspheres were worked up in the same manner as described in Example 1 to obtain a microsphere preparation containin~ y-interferon as a white powder having an average particle size of 100 ~m or less. All the above steps for the preparation were conducted aseptically.
Test Example 1 The effect of the sustained-release particulate preparation containing G-CSF prepared in Examples 1 and 2 above was tested using ~ister-Imamichi male rats (13 weeks-old). The test was conducted by withdrawing a blood sample for a control at 9 a.m. on the first day, and then admin-istering (1) a physiological saline solution which also contains 0.5% rat serum albumin and a 1% physiological saline solution of mannitol, (2) an aqueous solution of G-CSF as a control, or (3) the sustained-release particulate preparation of Example 1 or 2.
In this experiment, the test sample was administered subcutaneously or intramuscularly in the back-neck site of the rats according to the follo~ing schedule. That is, the physiological saline solution was administered in an amount of 0.5 ml/rat once a day for two weeks; the aqueous G-CSF
solution was administered in an amount of 0.5 ml/rat (2.5 ~g as G-CSF) once a day for two weeks; and each of the G-CSF-containing sustained-release particulate preparations obtained in Examples 1 and 2 was administered in an amount of 0.5 ml/rat (10 ~g as G-CSF) at a single dose, followed by evaluating the effect over a period of 2 weeks.
The evaluation of the effect was performed in terms of changes in the number of peripheral neutrocytes as compared with that of the aqueous G-CSF solution as a control. More specifically, an amount of erythrocytes, leukocytes and hemoglobin in the blosd sample withdrawn by ~uncture of the back medial branch of vein was determined using a microcell counter (Toa CC170 Model) and also the hemogram was obtained by a smear preparation of the blood sample. The number of neutrocytes was calculated as a 1 ~:L ~2~
product of the numbers of the leukocytes. The results obtained are shown in the accompanying drawings.
Figs. 1 and 2 illustrate graphs showing the amount of neutrocytes (x 102 cells/mm3 blood) over a period of two weeks obtained by administering the test sample. The graph "A" shows a result obtained by subcutaneous administration of the preparation of Example 1 (10 ~g G-CSF/rat/dose); the graph "B" shows the result obtained by intramuscular admin-istration of the preparation of Example 1 (10 ~g ~-CSF/
rat/~ose); the graph "C" shows the result obtained by subcutaneous administration of the preparation of Example 2 (10 ~g/rat/dose); the graph "D" shows the result obtained by subcutaneous administration of the physiological saline solution (0 ~g G-CSF/rat/day); and the graph "E" shows the result obtained by subcutaneous administration of the G-CSF
aqueous solution as a control (2.5 ~g/rat/day).
The results in Figs. 1 and 2 clearly demonstrate that the sustained-release particulate preparations according to the present invention exhibit the increase in the number of neutrocytes on every test day after administration to a degree which is substantially equivalent to or higher than that of the control.
As is apparent from the test results, the sustained-release particulate preparation according to the present invention is effective for preventing undesirable hydrolysis of physiologically active agents with enzymes after admin-istration which is often observed in usual injectable preparations, as well as for preventing polymerization of the active agent and the like. Further, the test results indicate that the sustained-release particulate preparation of this invention exhibits an effect substantially equiva-lent to or even higher than the effect obtained by the control at a lower dose level of the active agent than that of the control.
The sustained-release particulate preparation oE the present invention has a structure of microspheres or micro-capsules which can be used as an injection or a depo-type preparation, and is excellent in view of their uniformity in `` 13~2~
grain distribution, fineness of particles and surface smoothness of particles~ A~cordingly, the sustained-release particulate preparation of this invention is excepted to be useful for the treatment of various diseases since a constant blood level of the physiologically active agent can be maintained after administration of a single dose of the preparation and a long-lasting effect of the active agent can be obtained over a long period of time.
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
Claims (8)
1. A sustained-release particulate preparation consisting essentially of particles having a diameter not greater than 150 micrometers, which comprises a polymeric compound which is capable of being degraded in the living body and is compatible with living tissue, a pharmaceutically active agent which is water-insoluble or hardly soluble in water, and a natural hich molecular weight compound of sugar origin or a derivative thereof.
2. A sustained-release particulate preparation as claimed in claim 1, wherein said polymeric compound is polylactic acid, polyglycolic acid, polyhydroxybutyric acid or a copolymer thereof.
3. A sustained-release particulate preparation as claimed in claim 1, wherein said natural high molecular weight compound of sugar origin or a derivative thereof is selected from the group consisting of chitins and derivatives thereof, chitosans and derivatives thereof, hyaluronic acid and salts thereof, dextrans having a molecular weight of from about 10,000 to about 150,000, pectins, dextrins having a molecular weight of from about 2,500 to about 150,000, and chondroitin sulfate or a salt thereof.
4. A sustained-release particulate preparation as claimed in claim 1, wherein said pharmacologically active agent is an organic compound, a protein or a peptide which is water-insoluble or hardly soluble in water.
5. A method of making a sustained-release particulate preparation, which comprises the steps of:
a) combining an organic solution of a polymeric compound which is capable of being degraded in the living body and is compatible with living tissue, and an organic or organic/aqueous solution of a pharmaceutically active agent, which pharmaceutically active agent solution is capable of forming a solution, suspension or emulsion with said polymer solution and of forming a suspension in an aqueous solution;
b) combining the solution, suspension or emulsion of (a) with an aqueous solution of a natural high molecular weight compound of sugar origin or a derivative thereof, to form particles containing said pharmaceutically active agent and having a diameter not greater than 150 micrometers; and c) recovering said particles therefrom.
a) combining an organic solution of a polymeric compound which is capable of being degraded in the living body and is compatible with living tissue, and an organic or organic/aqueous solution of a pharmaceutically active agent, which pharmaceutically active agent solution is capable of forming a solution, suspension or emulsion with said polymer solution and of forming a suspension in an aqueous solution;
b) combining the solution, suspension or emulsion of (a) with an aqueous solution of a natural high molecular weight compound of sugar origin or a derivative thereof, to form particles containing said pharmaceutically active agent and having a diameter not greater than 150 micrometers; and c) recovering said particles therefrom.
6. A method as claimed in claim 5, wherein said polymeric compound is polylactic acid, polyglycolic acid, polyhydroxybutyric acid or a copolymer thereof.
7. A method as claimed in claim 5, wherein said natural high molecular weight compound of sugar origin or a derivative thereof is selected from the group consisting of chitins and derivatives thereof, chitosans and derivatives thereof, hyaluronic acid and salts thereof, dextrans having a molecular weight of from about 10,000 to about 150,000, pectins, dextrins having a molecular weight of from about 2,500 to about 150,000, and chondroitin sulfate or a salt thereof.
8. A method as claimed in claim 5, wherein said pharmacologically active agent is an organic compound, a protein or a peptide which is water-insoluble or hardly soluble in water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61237027A JPH0725689B2 (en) | 1986-10-07 | 1986-10-07 | Sustained-release preparation containing granulocyte colony-stimulating factor |
| JP237027/1986 | 1986-10-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1315200C true CA1315200C (en) | 1993-03-30 |
Family
ID=17009307
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000547960A Expired - Lifetime CA1315200C (en) | 1986-10-07 | 1987-10-06 | Sustained-release particulate preparation and process for preparing the same |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4853226A (en) |
| EP (1) | EP0263490B1 (en) |
| JP (1) | JPH0725689B2 (en) |
| KR (1) | KR930007247B1 (en) |
| AT (1) | ATE116540T1 (en) |
| AU (1) | AU608250B2 (en) |
| CA (1) | CA1315200C (en) |
| DE (1) | DE3750943T2 (en) |
| ES (1) | ES2068810T3 (en) |
| GR (1) | GR3015485T3 (en) |
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| DE3045135A1 (en) * | 1980-11-29 | 1982-06-09 | Sandoz-Patent-GmbH, 7850 Lörrach | BODEGRADABLE POLYMERS CONTAINING PHARMACEUTICAL COMPOSITIONS |
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-
1986
- 1986-10-07 JP JP61237027A patent/JPH0725689B2/en not_active Expired - Lifetime
-
1987
- 1987-10-06 KR KR1019870011169A patent/KR930007247B1/en not_active IP Right Cessation
- 1987-10-06 EP EP87114584A patent/EP0263490B1/en not_active Expired - Lifetime
- 1987-10-06 AT AT87114584T patent/ATE116540T1/en not_active IP Right Cessation
- 1987-10-06 ES ES87114584T patent/ES2068810T3/en not_active Expired - Lifetime
- 1987-10-06 AU AU79404/87A patent/AU608250B2/en not_active Expired
- 1987-10-06 CA CA000547960A patent/CA1315200C/en not_active Expired - Lifetime
- 1987-10-06 DE DE3750943T patent/DE3750943T2/en not_active Expired - Lifetime
- 1987-10-07 US US07/105,887 patent/US4853226A/en not_active Expired - Fee Related
-
1995
- 1995-03-20 GR GR950400616T patent/GR3015485T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2068810T3 (en) | 1995-05-01 |
| AU608250B2 (en) | 1991-03-28 |
| JPH0725689B2 (en) | 1995-03-22 |
| EP0263490B1 (en) | 1995-01-04 |
| DE3750943D1 (en) | 1995-02-16 |
| DE3750943T2 (en) | 1995-05-11 |
| AU7940487A (en) | 1988-04-14 |
| EP0263490A3 (en) | 1990-05-16 |
| KR880004802A (en) | 1988-06-27 |
| ATE116540T1 (en) | 1995-01-15 |
| US4853226A (en) | 1989-08-01 |
| JPS6391325A (en) | 1988-04-22 |
| GR3015485T3 (en) | 1995-06-30 |
| KR930007247B1 (en) | 1993-08-04 |
| EP0263490A2 (en) | 1988-04-13 |
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