CA2220871C - Peptide/protein suspending formulations - Google Patents
Peptide/protein suspending formulations Download PDFInfo
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- CA2220871C CA2220871C CA2220871A CA2220871A CA2220871C CA 2220871 C CA2220871 C CA 2220871C CA 2220871 A CA2220871 A CA 2220871A CA 2220871 A CA2220871 A CA 2220871A CA 2220871 C CA2220871 C CA 2220871C
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- 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
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Abstract
The present invention provides improved compositions for improving the chemical and physical stability of peptides and proteins. The invention provides a liquid beneficial agent formulation containing a liquid suspension comprising at least 5 % by weight beneficial agent and having a viscosity and beneficial agent size which minimizes setting of the agent in suspension over the extended delivery period.
Description
This invention relates to stabilized, concentrated suspensions 6 formulations of peptides and proteins. More particularly, this invention relates 7 to novel and improved compositions for providing concentrated, non-aqueous 8 suspensions of peptides/proteins for pharmaceutical use having adequate 9 chemical, physical and bioactive stability suitable for long term delivery from a sustained release drug delivery system.
14 Proteins, as well as many other biologically active compounds, degrade over time in aqueous solution. Because of this chemical instability, 16 protein solutions are often not suitable for use in drug delivery devices.
17 Carriers, in which proteins do not dissolve but rather are suspended, 18 can often offer improved chemical stability. Furthermore, it can be beneficial 19 to suspend the beneficial agent in a carrier when the agent exhibits low 21) solubility in the desired vehicle. However, suspensions can have poor 21 physical stability due to settling and agglomeration of the suspended 22 beneficial agent. The problems with non-aqueous carriers tend to be 23 exacerbated as the concentration of the active compound is increased.
24 For drug delivering implants, dosing durations of up to one year are not unusual. Beneficial agents which have low therapeutic delivery rates 26 are prime candidates for use in implants. When the device is implanted or 27 stored, settling of the beneficial agent in the liquid formulation can occur.
26 This heterogeneity can adversely effect the concentration of the beneficial 29 agent dispensed. Compounding this problem is the size of the implanted beneficial agent reservoir. Implant reservoirs are generally on the order of 1 25-250 l. With this volume restriction, a formulation of high concentration 2 (greater than or equal to 10%) and a minimum amount of suspension vehicle 3 and other excipients is preferred.
4 Alpha interferon (a-IFN) is one example of a beneficial agent which provides a therapeutic effect at a low dose. This interferon is indicated in the 6 treatment of chronic hepatitis because of its antiviral activity. Prescribed 7 therapy presently entails injections of a-IFN solution, containing about 8 3.0 x 106 IU (15 micrograms) of agent per dose, three times per week for a 9 4 to 6 month period. Frequent injections are required because of the short elimination half-life of a-IFN; most of the drug being completely cleared from 11 the plasma within eight to ten hours after the injection.
12 U.S. Pat. Nos. 4,871,538 issued to Yim et al; 4,847,079 issued to 13 Kwan et al; 5,081,156 issued to Yamashira et al, and European Publication 14 No. 0,281,299 issued to Yim et al describe IFN /peptide compositions with concentrations between 104 to 108IU/mi. In Kwan et aI, a pharmaceutical 16 solution having a a-IFN concentration of 103 to 108 IU/ml is described.
17 Yim describes a dosage range being between 104 to 108 IU a-IFN/ml.
18 In Yim II, an insoluble complex including a-IFN, zinc, and protamine is 19 suspended in a phosphate buffer. Yim I, Yim II, and Kwan, however, teach the use, in part, of an aqueous buffer in their compositions. This leads to 21 possible hydrolysis of the compound, leading to chemical degradation and 22 instability. Yamashira teaches a sustained release preparation of interferon in 23 a mixture with a biodegradable carrier. IFN is incorporated at concentrations 24 of 103 to 108 IU per 1 mg of carrier or, alternatively, each dosage form containing 104 to 108 IU of interferon. Furthermore, while the patents and 26 publications described above describe concentrations between 104 to 108 27 IU/ml, none describe concentrations on the order of 109 to 1011 IU/ml.
1 There is a need for a novel composition comprising a nonaqueous 2 suspension vehicle and concentrated protein/peptide as the beneficial agent 3 for use in implanted, sustained release devices. While it is known in the art to 4 achieve stable a IFN concentrations of up to 108 IU/ml, this invention utilizes a novel combination whose combined effect produces a significant and 6 surprising improvement in the physical and chemical stability of the beneficial 7 agent compound over other formulations.
11 FIG. 1 is a cross-section of an implantable sustained release osmotic 12 delivery device for use in combination with the concentrated suspensions of 13 the present invention.
1.4 FIG. 2 is a graph illustrating the stability of a cytochrome c suspension.
FIG. 3 is a graph illustrating the stability of an a-interferon suspension.
1;r DESCRIPTION OF THE INVENTION
19 One aspect of this invention relates to preparations for stabilizing peptides and proteins at high concentrations for extended periods of time.
21 Another aspect of this invention relates to stabilized preparations of 22 human a-IFN.
23 Another aspect of this invention relates to stabilized preparations of 24 human a-IFN having concentrations of at least I x 109 IU/mi.
Another aspect of this invention relates to stabilizing beneficial agent 26 formulations comprising a beneficial agent having a particle size of between 27 0.3 to 50 microns and suspension vehicle formula having a viscosity between 28 100 to 100,000 poise at 37 C.
3a According to a preferred embodiment of the present invention, there is provided a beneficial agent formulation for use in a device which delivers the formulation over an extended delivery period, the formulation comprising a suspension containing at least 5% by weight beneficial agent in the form of solid particles, the beneficial agent particle size being 0.3 to 50 microns and the suspension viscosity being sufficient to prevent settling of the agent in the suspension formulation over the extended delivery period.
1 The new formulations are physically stable suspensions which provide 2 chemical stability to water sensitive compounds and can be employed to 3 stabilize high concentrations of the active compound. The carrier 4 components are acceptable for use in implantable systems.
8 The concentrated beneficial agent suspensions of the present 9 invention provide significantly stable concentrations over extended periods of time, useful for sustained delivery, implant applications. The suspensions of 11 this invention minimize the particle degradation due to hydrolysis and particle 12 settling over the duration of the extended delivery period. These extended 13 periods of time are between one week to two years, preferably between three 14 months to one year.
The sustained parenteral delivery of drugs provides many advantages.
16 Typical sustained release implantable osmotic delivery devices are 17 described in U.S. Pat. Nos. 5,034,229; 5,057,318; and 5,110,596 .
18 As shown in Fig. 1, these devices 10 19 typically comprise a housing 12 including a fluid impermeable wall section and a fluid permeable wall section 16 which sections define and surround an 21 internal compartment 18. An exit passageway 20 is formed within the fluid 22 impermeable wall section to fluidly communicate the internal compartment 18 23 with the external environment. To minimize exposure to the environmental 24 fluids, a beneficial agent 22 is contained within the fluid impermeable section.
An expandable driving member 24, contained within the fluid permeable 26 section, expands with the imbibition of fluid across the fluid permeable wall 27 section. Typically a piston 26 separates the beneficial agent 22 from the 28 expandable driving member 24. This forces the agent out through the exit 1 passageway and into the environment of use. The non-aqueous 2 administration of a beneficial agent in the suspension formulation as 3 disclosed herein can be accomplished using implant devices of these kinds.
4 According to this invention, high concentrations of the beneficial agent 5 remain suspended, and physically and chemically stable in a non-aqueous 6 suspension vehicle. "High concentration" is defined as the beneficial agent 7 concentration level of at least about 0.5 wt% of the formulation, preferably 6 at least about 5 wt% and most preferably between about 10 to 70% w/w.
9 For example, "high concentrations" of a-IFN are 109 to 1011 IU; and for salmon calcitonin, concentrations of between 2 x 104 lU to 2.8 x 106 IU
i t are "high concentrations". The beneficial agent particle size is between 12 0.3 to 50 microns, and preferably about 1-10 microns in diameter. Desired 13 particle size can be provided typically by milling, sieving, spray drying, 14 supercritical fluid extraction of the particular beneficial agent selected.
is Typical beneficial agents for use in this device and composition include the 16 interferons and calcitonin. Other representative beneficial agents that can be 17 administered include pharmacologically active peptides and proteins, anabolic 18 hormones, growth promoting hormones, hormones related to the endocrine 19 system comprising porcine growth promoting hormone, bovine growth promoting hormone, equine growth promoting hormone, ovine growth 21 promoting hormone, human growth promoting hormone, growth promoting 22 hormones derived by extraction and concentration from pituitary and 23 hypothalmus glands, growth promoting hormones produced by recombinant 24 DNA methods, bovine growth promoting hormone as described in Nucleic Acid Res., Vol. 10, p 7197 (1982), ovine growth promoting hormone as 26 described in Arch. Biochem. Biophys., Vol. 156, p 493 (1973), and porcine 27 growth promoting hormone as described in DNA, Vol. 2, pp 37, 45, (1983).
28 Representative beneficial agents also comprise cochicine, cosyntropin, 29 and lypressin. The polypeptides also comprise growth hormone, somatropin, somatotropin, somatotropin analogues, modified porcine somatotropin, 1 modified bovine somatotropin, derivatives of both porcine and bovine 2 somatotropin, somatomedin-C, gonadotropic releasing hormone, follicle 3 stimulating hormone, luteinizing hormone, LH-RH, LH-RH analogs, growth 4 hormone releasing factor, gonadotropin releasing factor, insulin, chorionic gonadotropin, oxytocin, somatotropin plus an amino acid, vasopressin, 6 adrenocorticotrophic hormone, epidermal growth factor, prolactin, 7 somatostatin, somatotropin plus a protein, polypeptides such as thyrotropin 8 releasing hormone, thyroid stimulating hormone, secretin, pancreozymin, 9 enkephalin, glucagon, endocrine agents secreted internally and distributed in an animal by way of the bloodstream, and the like. The beneficial agents and 11 their dosage unit amounts are known to the prior art in The Pharmacological 12 Basis of Therapeutics, by Gilman, Goodman, Rall and Murad, 7th Ed., (1985) 13 published by MacMillan Publishing Co., NY; in Pharmaceutical Sciences, 14 Remington, 17th Ed., (1985) published by Mack Publishing Co., Easton, PA, and in U.S. Pat. No. 4,526,938. Particularly preferred are beneficial agents 16 which produce the desired therapeutic effect at a low delivery rate/dose, 17 for example, proteins/peptides which require picograms to milligrams of 18 agent.
19 A pharmaceutically acceptable suspension vehicle is used to suspend the solid beneficial agent particles in the beneficial agent formulation.
21 Non-aqueous vehicles are used to isolate the beneficial agent from water and 22 prevent hydrolysis or other degradation of the beneficial agent while in 23 suspension. Furthermore, pharmaceutically acceptable suspension vehicles 24 may function as a thickening agent for the components present in an implant.
As a vehicle for transporting beneficial agents from the implant, it provides 26 protection against the decomposition of a beneficial agent, and it imparts 27 physical and chemical stability to components present in the formulation.
28 The thickening agent may be used to increase the viscosity of the formulation 29 to prevent fluids in the implantation environment from mixing with the 1 implant's beneficial agent formulation. The amount of thickening agent 2 present in the formulation is between 1 % to 99.9% and preferably 5-60%
3 depending upon the viscosity adjustment needed.
4 Typical non-aqueous suspension vehicles include: waxes, which have a softening temperature at or less than body temperature; hydrogenated 6 vegetable oils, (e.g., peanut oil, cottonseed oil, sesame oil, castor oil, olive oil, 7 corn oil, Iodinated poppy seed oils) silicon oil, medium chain fatty acid 8 monoglycerides, or polyols. Of these polyols are preferred.
9 Polyols suitable for suspension vehicles include such as diol, triol, polyhydric alcohol, and the like. More specific polyols comprise polyethylene 11 glycol (average molecular weight between 200 and 1000), propylene glycol, 12 polyethylene glycol 1,5-pentylene glycol; 1,6-hexylene glycol; 1,7-heptylene 13 glycol; 1,9-nonylene glycol; 1,2-dimethyl-1,6-hexylene glycol;
14 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol;
dipentaerythriol, and the like. In another embodiment the pharmaceutically 16 acceptable suspension vehicle comprises glycerol mono(lower alkyl) ethers 17 and glycerol di(lower alkyl) ethers such as glycerol 1-methyl ether;
glycerol 18 1-ethyl ether; glycerol 1,2-dimethyl ether; glycerol 1,3-dimethyl ether, 19 and the like. In another embodiment the pharmaceutically acceptable vehicle :20 comprises a mixture such as propylene glycol and glycero, and the like.
:21 Sufficient viscosity is required to suspend the particles in the carrier 22 throughout the duration of the extended delivery period. Settling is a function 23 of the particle size and the carrier viscosity. If the duration of the delivery 24 period is shorter, the viscosity can be lower since the time required to be I suspended is shorter. The viscosity required, for example, can be determined 2 by the Stokes-Einstein equation which is a measure of how far a particle in 3 suspension will travel V= 2gR2 (Pp Po) 9 V = velocity of settling p. = viscosity of the carrier 11 g = acceleration due to gravity 12 PP = density of particle 13 Pc = density of carrier wherein R = the average particle radius of the beneficial agent. The viscosity 16 of the beneficial agent suspending formulation can be altered by the use of 17 thickening agents to raise the viscosity to the desired level. Typical 18 thickening agents for use in the compositions of this invention include suitable 19 hydrogels such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, polyacrylic acid, poly(methyl 21 methacrylic acid) (PMMA). Preferred hydrogels are cellulose ethers such as 22 hydroxyalkylcellulose and hydroxyalkylalkyl-cellulose compounds. A most 23 preferred hydroxyalkylcellulose is hydroxypropyl cellulose (HPC) and 24 povidone (PVP). Hydroxypropyl cellulose is commercially available in a wide range of viscosity grades sold under the tradename Klucel TM (Hercules, Ltd., 26 London, England). The concentration of the hydroxyalkylcellulose is 27 dependent upon the particular viscosity grade used and the desired viscosity 28 of the liquid composition. For example, where the desired viscosity is less 29 than about 1000 poise (cps), hydroxypropyl cellulose having an average molecular weight of about 60,000 daltons (i.e., Klucel EF TM) can be used.
31 Where the desired viscosity is from about 1000 to about 2500 cps, higher 32 viscosity grades of hydroxypropyl cellulose can be used (i.e., Klucel LF TM
and 33 Lucel GF TM). In addition to using different viscosities of different thickening 1 agents, using different amounts of the same particular thickening agent can 2 be used to vary the viscosity. Preferably, the concentration of hydroxypropyl 3 cellulose is from 5 percent w/w and, more preferably from 5 to 20 %w/w of the 4 carrier and most preferably between 8-18 %w/w. Aluminum monostearate can be used as a thickening agent if oils are used as the carrier.
6 Hydroxyalkylalkylcellulose ethers are a class of water-soluble 7 hydrogels derived from etherification of cellulose. As used herein in reference a to this class of hydrogels, the term "alkyl" means C1-C5 alkyl where alkyl 9 refers to linear or branched chains having 1 to 6 carbon atoms, which can be 11) optionally substituted as herein defined. Representative alkyl groups include 1 li methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like.
12 Exemplary hydroxyalkylalkylcelluloses are hydroxypropylmethyl 13 cellulose, hydroxyethylmethyl cellulose and hydroxybutylmethyl cellulose.
14. Hydroxypropylmethyl cellulose (HPMC) is preferred. HPMC is commercially available (i.e., Aldrich Chem. Co., Ltd. Dorset, England and Dow Chem. Co., 16 Midland, Mich., USA) in a wide range of viscosity grades. In addition to 17 increasing viscosity, hydroxyalkylalkylcelluloses can serve as a stabilizing, 18 suspending and emulsifying agent. The concentration of 19 hydroxyalkylalkylcellulose in a liquid composition of this invention is dependent inter alia on its intended use (i.e., stabilizer, emulsifier, 21 viscosity-increasing agent) and its viscosity grade.
22 To assure the viscosity of the suspension vehicle is sufficient to 23 maintain the agent in suspension over the desired delivery period, thickening 24 agents can be added to the suspension vehicle. The preferred thickening agents include povidone and hydroxypropyl cellulose. In one embodiment, 26 when the PEG utilized is a low molecular weight, e.g., 400, 5%
hydroxypropyl 27 cellulose, having an average molecular weight of 1000, or 40 -60% povidone 28 can be used in combination with a balance of polyethylene glycol. If the 1 polyethylene glycol utilized in the suspension vehicle has a molecular weight 2 of greater than 600, e.g., 1000 molecular weight, povidone is preferably 3 utilized as the thickening agent.
4 The following examples are offered to illustrate the practice of the 5 present invention and are not intended to limit the invention in any manner.
9 A viscous carrier was prepared containing 50% PEG 400 and 10 50% povidone (PVP) by weight. PEG 400 (Union Carbide) was weighed 11 into a beaker and an equal weight of povidone K29-32 (GAF) was added.
14 Proteins, as well as many other biologically active compounds, degrade over time in aqueous solution. Because of this chemical instability, 16 protein solutions are often not suitable for use in drug delivery devices.
17 Carriers, in which proteins do not dissolve but rather are suspended, 18 can often offer improved chemical stability. Furthermore, it can be beneficial 19 to suspend the beneficial agent in a carrier when the agent exhibits low 21) solubility in the desired vehicle. However, suspensions can have poor 21 physical stability due to settling and agglomeration of the suspended 22 beneficial agent. The problems with non-aqueous carriers tend to be 23 exacerbated as the concentration of the active compound is increased.
24 For drug delivering implants, dosing durations of up to one year are not unusual. Beneficial agents which have low therapeutic delivery rates 26 are prime candidates for use in implants. When the device is implanted or 27 stored, settling of the beneficial agent in the liquid formulation can occur.
26 This heterogeneity can adversely effect the concentration of the beneficial 29 agent dispensed. Compounding this problem is the size of the implanted beneficial agent reservoir. Implant reservoirs are generally on the order of 1 25-250 l. With this volume restriction, a formulation of high concentration 2 (greater than or equal to 10%) and a minimum amount of suspension vehicle 3 and other excipients is preferred.
4 Alpha interferon (a-IFN) is one example of a beneficial agent which provides a therapeutic effect at a low dose. This interferon is indicated in the 6 treatment of chronic hepatitis because of its antiviral activity. Prescribed 7 therapy presently entails injections of a-IFN solution, containing about 8 3.0 x 106 IU (15 micrograms) of agent per dose, three times per week for a 9 4 to 6 month period. Frequent injections are required because of the short elimination half-life of a-IFN; most of the drug being completely cleared from 11 the plasma within eight to ten hours after the injection.
12 U.S. Pat. Nos. 4,871,538 issued to Yim et al; 4,847,079 issued to 13 Kwan et al; 5,081,156 issued to Yamashira et al, and European Publication 14 No. 0,281,299 issued to Yim et al describe IFN /peptide compositions with concentrations between 104 to 108IU/mi. In Kwan et aI, a pharmaceutical 16 solution having a a-IFN concentration of 103 to 108 IU/ml is described.
17 Yim describes a dosage range being between 104 to 108 IU a-IFN/ml.
18 In Yim II, an insoluble complex including a-IFN, zinc, and protamine is 19 suspended in a phosphate buffer. Yim I, Yim II, and Kwan, however, teach the use, in part, of an aqueous buffer in their compositions. This leads to 21 possible hydrolysis of the compound, leading to chemical degradation and 22 instability. Yamashira teaches a sustained release preparation of interferon in 23 a mixture with a biodegradable carrier. IFN is incorporated at concentrations 24 of 103 to 108 IU per 1 mg of carrier or, alternatively, each dosage form containing 104 to 108 IU of interferon. Furthermore, while the patents and 26 publications described above describe concentrations between 104 to 108 27 IU/ml, none describe concentrations on the order of 109 to 1011 IU/ml.
1 There is a need for a novel composition comprising a nonaqueous 2 suspension vehicle and concentrated protein/peptide as the beneficial agent 3 for use in implanted, sustained release devices. While it is known in the art to 4 achieve stable a IFN concentrations of up to 108 IU/ml, this invention utilizes a novel combination whose combined effect produces a significant and 6 surprising improvement in the physical and chemical stability of the beneficial 7 agent compound over other formulations.
11 FIG. 1 is a cross-section of an implantable sustained release osmotic 12 delivery device for use in combination with the concentrated suspensions of 13 the present invention.
1.4 FIG. 2 is a graph illustrating the stability of a cytochrome c suspension.
FIG. 3 is a graph illustrating the stability of an a-interferon suspension.
1;r DESCRIPTION OF THE INVENTION
19 One aspect of this invention relates to preparations for stabilizing peptides and proteins at high concentrations for extended periods of time.
21 Another aspect of this invention relates to stabilized preparations of 22 human a-IFN.
23 Another aspect of this invention relates to stabilized preparations of 24 human a-IFN having concentrations of at least I x 109 IU/mi.
Another aspect of this invention relates to stabilizing beneficial agent 26 formulations comprising a beneficial agent having a particle size of between 27 0.3 to 50 microns and suspension vehicle formula having a viscosity between 28 100 to 100,000 poise at 37 C.
3a According to a preferred embodiment of the present invention, there is provided a beneficial agent formulation for use in a device which delivers the formulation over an extended delivery period, the formulation comprising a suspension containing at least 5% by weight beneficial agent in the form of solid particles, the beneficial agent particle size being 0.3 to 50 microns and the suspension viscosity being sufficient to prevent settling of the agent in the suspension formulation over the extended delivery period.
1 The new formulations are physically stable suspensions which provide 2 chemical stability to water sensitive compounds and can be employed to 3 stabilize high concentrations of the active compound. The carrier 4 components are acceptable for use in implantable systems.
8 The concentrated beneficial agent suspensions of the present 9 invention provide significantly stable concentrations over extended periods of time, useful for sustained delivery, implant applications. The suspensions of 11 this invention minimize the particle degradation due to hydrolysis and particle 12 settling over the duration of the extended delivery period. These extended 13 periods of time are between one week to two years, preferably between three 14 months to one year.
The sustained parenteral delivery of drugs provides many advantages.
16 Typical sustained release implantable osmotic delivery devices are 17 described in U.S. Pat. Nos. 5,034,229; 5,057,318; and 5,110,596 .
18 As shown in Fig. 1, these devices 10 19 typically comprise a housing 12 including a fluid impermeable wall section and a fluid permeable wall section 16 which sections define and surround an 21 internal compartment 18. An exit passageway 20 is formed within the fluid 22 impermeable wall section to fluidly communicate the internal compartment 18 23 with the external environment. To minimize exposure to the environmental 24 fluids, a beneficial agent 22 is contained within the fluid impermeable section.
An expandable driving member 24, contained within the fluid permeable 26 section, expands with the imbibition of fluid across the fluid permeable wall 27 section. Typically a piston 26 separates the beneficial agent 22 from the 28 expandable driving member 24. This forces the agent out through the exit 1 passageway and into the environment of use. The non-aqueous 2 administration of a beneficial agent in the suspension formulation as 3 disclosed herein can be accomplished using implant devices of these kinds.
4 According to this invention, high concentrations of the beneficial agent 5 remain suspended, and physically and chemically stable in a non-aqueous 6 suspension vehicle. "High concentration" is defined as the beneficial agent 7 concentration level of at least about 0.5 wt% of the formulation, preferably 6 at least about 5 wt% and most preferably between about 10 to 70% w/w.
9 For example, "high concentrations" of a-IFN are 109 to 1011 IU; and for salmon calcitonin, concentrations of between 2 x 104 lU to 2.8 x 106 IU
i t are "high concentrations". The beneficial agent particle size is between 12 0.3 to 50 microns, and preferably about 1-10 microns in diameter. Desired 13 particle size can be provided typically by milling, sieving, spray drying, 14 supercritical fluid extraction of the particular beneficial agent selected.
is Typical beneficial agents for use in this device and composition include the 16 interferons and calcitonin. Other representative beneficial agents that can be 17 administered include pharmacologically active peptides and proteins, anabolic 18 hormones, growth promoting hormones, hormones related to the endocrine 19 system comprising porcine growth promoting hormone, bovine growth promoting hormone, equine growth promoting hormone, ovine growth 21 promoting hormone, human growth promoting hormone, growth promoting 22 hormones derived by extraction and concentration from pituitary and 23 hypothalmus glands, growth promoting hormones produced by recombinant 24 DNA methods, bovine growth promoting hormone as described in Nucleic Acid Res., Vol. 10, p 7197 (1982), ovine growth promoting hormone as 26 described in Arch. Biochem. Biophys., Vol. 156, p 493 (1973), and porcine 27 growth promoting hormone as described in DNA, Vol. 2, pp 37, 45, (1983).
28 Representative beneficial agents also comprise cochicine, cosyntropin, 29 and lypressin. The polypeptides also comprise growth hormone, somatropin, somatotropin, somatotropin analogues, modified porcine somatotropin, 1 modified bovine somatotropin, derivatives of both porcine and bovine 2 somatotropin, somatomedin-C, gonadotropic releasing hormone, follicle 3 stimulating hormone, luteinizing hormone, LH-RH, LH-RH analogs, growth 4 hormone releasing factor, gonadotropin releasing factor, insulin, chorionic gonadotropin, oxytocin, somatotropin plus an amino acid, vasopressin, 6 adrenocorticotrophic hormone, epidermal growth factor, prolactin, 7 somatostatin, somatotropin plus a protein, polypeptides such as thyrotropin 8 releasing hormone, thyroid stimulating hormone, secretin, pancreozymin, 9 enkephalin, glucagon, endocrine agents secreted internally and distributed in an animal by way of the bloodstream, and the like. The beneficial agents and 11 their dosage unit amounts are known to the prior art in The Pharmacological 12 Basis of Therapeutics, by Gilman, Goodman, Rall and Murad, 7th Ed., (1985) 13 published by MacMillan Publishing Co., NY; in Pharmaceutical Sciences, 14 Remington, 17th Ed., (1985) published by Mack Publishing Co., Easton, PA, and in U.S. Pat. No. 4,526,938. Particularly preferred are beneficial agents 16 which produce the desired therapeutic effect at a low delivery rate/dose, 17 for example, proteins/peptides which require picograms to milligrams of 18 agent.
19 A pharmaceutically acceptable suspension vehicle is used to suspend the solid beneficial agent particles in the beneficial agent formulation.
21 Non-aqueous vehicles are used to isolate the beneficial agent from water and 22 prevent hydrolysis or other degradation of the beneficial agent while in 23 suspension. Furthermore, pharmaceutically acceptable suspension vehicles 24 may function as a thickening agent for the components present in an implant.
As a vehicle for transporting beneficial agents from the implant, it provides 26 protection against the decomposition of a beneficial agent, and it imparts 27 physical and chemical stability to components present in the formulation.
28 The thickening agent may be used to increase the viscosity of the formulation 29 to prevent fluids in the implantation environment from mixing with the 1 implant's beneficial agent formulation. The amount of thickening agent 2 present in the formulation is between 1 % to 99.9% and preferably 5-60%
3 depending upon the viscosity adjustment needed.
4 Typical non-aqueous suspension vehicles include: waxes, which have a softening temperature at or less than body temperature; hydrogenated 6 vegetable oils, (e.g., peanut oil, cottonseed oil, sesame oil, castor oil, olive oil, 7 corn oil, Iodinated poppy seed oils) silicon oil, medium chain fatty acid 8 monoglycerides, or polyols. Of these polyols are preferred.
9 Polyols suitable for suspension vehicles include such as diol, triol, polyhydric alcohol, and the like. More specific polyols comprise polyethylene 11 glycol (average molecular weight between 200 and 1000), propylene glycol, 12 polyethylene glycol 1,5-pentylene glycol; 1,6-hexylene glycol; 1,7-heptylene 13 glycol; 1,9-nonylene glycol; 1,2-dimethyl-1,6-hexylene glycol;
14 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol;
dipentaerythriol, and the like. In another embodiment the pharmaceutically 16 acceptable suspension vehicle comprises glycerol mono(lower alkyl) ethers 17 and glycerol di(lower alkyl) ethers such as glycerol 1-methyl ether;
glycerol 18 1-ethyl ether; glycerol 1,2-dimethyl ether; glycerol 1,3-dimethyl ether, 19 and the like. In another embodiment the pharmaceutically acceptable vehicle :20 comprises a mixture such as propylene glycol and glycero, and the like.
:21 Sufficient viscosity is required to suspend the particles in the carrier 22 throughout the duration of the extended delivery period. Settling is a function 23 of the particle size and the carrier viscosity. If the duration of the delivery 24 period is shorter, the viscosity can be lower since the time required to be I suspended is shorter. The viscosity required, for example, can be determined 2 by the Stokes-Einstein equation which is a measure of how far a particle in 3 suspension will travel V= 2gR2 (Pp Po) 9 V = velocity of settling p. = viscosity of the carrier 11 g = acceleration due to gravity 12 PP = density of particle 13 Pc = density of carrier wherein R = the average particle radius of the beneficial agent. The viscosity 16 of the beneficial agent suspending formulation can be altered by the use of 17 thickening agents to raise the viscosity to the desired level. Typical 18 thickening agents for use in the compositions of this invention include suitable 19 hydrogels such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, polyacrylic acid, poly(methyl 21 methacrylic acid) (PMMA). Preferred hydrogels are cellulose ethers such as 22 hydroxyalkylcellulose and hydroxyalkylalkyl-cellulose compounds. A most 23 preferred hydroxyalkylcellulose is hydroxypropyl cellulose (HPC) and 24 povidone (PVP). Hydroxypropyl cellulose is commercially available in a wide range of viscosity grades sold under the tradename Klucel TM (Hercules, Ltd., 26 London, England). The concentration of the hydroxyalkylcellulose is 27 dependent upon the particular viscosity grade used and the desired viscosity 28 of the liquid composition. For example, where the desired viscosity is less 29 than about 1000 poise (cps), hydroxypropyl cellulose having an average molecular weight of about 60,000 daltons (i.e., Klucel EF TM) can be used.
31 Where the desired viscosity is from about 1000 to about 2500 cps, higher 32 viscosity grades of hydroxypropyl cellulose can be used (i.e., Klucel LF TM
and 33 Lucel GF TM). In addition to using different viscosities of different thickening 1 agents, using different amounts of the same particular thickening agent can 2 be used to vary the viscosity. Preferably, the concentration of hydroxypropyl 3 cellulose is from 5 percent w/w and, more preferably from 5 to 20 %w/w of the 4 carrier and most preferably between 8-18 %w/w. Aluminum monostearate can be used as a thickening agent if oils are used as the carrier.
6 Hydroxyalkylalkylcellulose ethers are a class of water-soluble 7 hydrogels derived from etherification of cellulose. As used herein in reference a to this class of hydrogels, the term "alkyl" means C1-C5 alkyl where alkyl 9 refers to linear or branched chains having 1 to 6 carbon atoms, which can be 11) optionally substituted as herein defined. Representative alkyl groups include 1 li methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like.
12 Exemplary hydroxyalkylalkylcelluloses are hydroxypropylmethyl 13 cellulose, hydroxyethylmethyl cellulose and hydroxybutylmethyl cellulose.
14. Hydroxypropylmethyl cellulose (HPMC) is preferred. HPMC is commercially available (i.e., Aldrich Chem. Co., Ltd. Dorset, England and Dow Chem. Co., 16 Midland, Mich., USA) in a wide range of viscosity grades. In addition to 17 increasing viscosity, hydroxyalkylalkylcelluloses can serve as a stabilizing, 18 suspending and emulsifying agent. The concentration of 19 hydroxyalkylalkylcellulose in a liquid composition of this invention is dependent inter alia on its intended use (i.e., stabilizer, emulsifier, 21 viscosity-increasing agent) and its viscosity grade.
22 To assure the viscosity of the suspension vehicle is sufficient to 23 maintain the agent in suspension over the desired delivery period, thickening 24 agents can be added to the suspension vehicle. The preferred thickening agents include povidone and hydroxypropyl cellulose. In one embodiment, 26 when the PEG utilized is a low molecular weight, e.g., 400, 5%
hydroxypropyl 27 cellulose, having an average molecular weight of 1000, or 40 -60% povidone 28 can be used in combination with a balance of polyethylene glycol. If the 1 polyethylene glycol utilized in the suspension vehicle has a molecular weight 2 of greater than 600, e.g., 1000 molecular weight, povidone is preferably 3 utilized as the thickening agent.
4 The following examples are offered to illustrate the practice of the 5 present invention and are not intended to limit the invention in any manner.
9 A viscous carrier was prepared containing 50% PEG 400 and 10 50% povidone (PVP) by weight. PEG 400 (Union Carbide) was weighed 11 into a beaker and an equal weight of povidone K29-32 (GAF) was added.
12 The PEG and povidone were mixed by stirring with a spatula for about 13 5 minutes. The blended carrier was allowed to sit overnight to insure 14 complete dissolution of the povidone. The carrier was then deaerated in a vacuum oven (National Appliance Company) by drawing a vacuum and 16 holding the carrier at 50 C for 30 minutes.
17 Cytochrome c (Sigma, from horseheart) was milled in a jar mill and 18 then passed through a 400 mesh screen to produce a particle diameter of 19 less than 37 micron. In a beaker, 0.5566 grams of the cytochrome c was added to 4.9970 grams of the PEG 400/povidone carrier to prepare a 10%
21 cytochrome c suspension in 50:50 PVP:PEG 400 carrier. The suspension 22 was thoroughly blended by mixing with a spatula for about 5 minutes.
23 The cytochrome c suspension was then loaded into 11 osmotic veterinary 24 implants (as in Figure 1).
The implants were tested in vitro by releasing into culture tubes filled 26 with deionized water. To monitor release of cytochrome c from the implants, 27 samples of the release media were assayed on a UV spectrophotometer 28 (Shimadzu UV 160U) at a wavelength of 409 nm. The implants delivered the 29 cytochrome c successfully over the designed duration of the implant 1 (42 days). Fig. 2 is a graph that illustrates the cumulative protein delivery 2 (mg) over time. During the later half of the release period, several implants 3 were removed from the tubes and examined to determine whether settling of 4 the cytochrome c had occurred. These implants were sectioned and samples of the protein suspension were removed from the top and bottom portions of 6 the implant. The samples of the protein suspension were weighed, diluted 7 with DI water in volumetric flasks and assayed via UV a spectrophotometer.
8 Results indicated that the cytochrome c suspension was homogeneous.
12 Standard : 20 l of a 8.0 mg/ml standard was diluted to 160 g/ml.
13 Each HPLC sample was diluted by a factor of 10 into distilled water.
14 The operating conditions of the HPLC were as follows:
Column: POROS RH 2.1 mm x 3.0 cm 16 Mobile phase: A: 95% H2O, 0.1 % TFA, 5% ACN
17 B: 95% ACN, 5% H2O, 0.083% TFA
18 Gradient: 20% B to 50% B in 5 minutes 19 Flow: 2.0 ml/min Detector: 280 nm @ 0.002 AUFS
21 IRMA Standards: Working standards were prepared by diluting IRMA
22 standards into phosphate buffered saline (PBS) containing 0.5% Bovine 23 Serum Albumin (BSA). Samples were prepared by serially diluting by factors 24 of 400 for interferon formulations and 2000 for the standard into PBS
containing 0.5% BSA.
26 Figure 3 shows the results of the HPLC and the IRMA assays.
27 The HPLC measurements indicate no losses of the a-IFN over 5 days, even 28 at 37 C, indicating stability of this protein in non-aqueous vehicle.
Relative 29 to the initial stock solution, the activity shown by IRMA at t = 0 is 78%.
*Trade-mark 1 At t = 5 days, the formulation displayed an activity of 87% at room 2 temperature and 90% at 37 C. When compared to the original stock, 3 no losses of a-IFN were detected by HPLC in this formulation. Stability 4 of interferon in PEG over 5 days at 37 C was indicated by this assay. =
However, approximately 80 - 90% of the activity of the initial stock was 6 maintained. The IRMA readings suggest no activity losses due to time and 7 temperature effects.
8 This invention has been described in detail with particular reference 9 to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of 11 the invention.
17 Cytochrome c (Sigma, from horseheart) was milled in a jar mill and 18 then passed through a 400 mesh screen to produce a particle diameter of 19 less than 37 micron. In a beaker, 0.5566 grams of the cytochrome c was added to 4.9970 grams of the PEG 400/povidone carrier to prepare a 10%
21 cytochrome c suspension in 50:50 PVP:PEG 400 carrier. The suspension 22 was thoroughly blended by mixing with a spatula for about 5 minutes.
23 The cytochrome c suspension was then loaded into 11 osmotic veterinary 24 implants (as in Figure 1).
The implants were tested in vitro by releasing into culture tubes filled 26 with deionized water. To monitor release of cytochrome c from the implants, 27 samples of the release media were assayed on a UV spectrophotometer 28 (Shimadzu UV 160U) at a wavelength of 409 nm. The implants delivered the 29 cytochrome c successfully over the designed duration of the implant 1 (42 days). Fig. 2 is a graph that illustrates the cumulative protein delivery 2 (mg) over time. During the later half of the release period, several implants 3 were removed from the tubes and examined to determine whether settling of 4 the cytochrome c had occurred. These implants were sectioned and samples of the protein suspension were removed from the top and bottom portions of 6 the implant. The samples of the protein suspension were weighed, diluted 7 with DI water in volumetric flasks and assayed via UV a spectrophotometer.
8 Results indicated that the cytochrome c suspension was homogeneous.
12 Standard : 20 l of a 8.0 mg/ml standard was diluted to 160 g/ml.
13 Each HPLC sample was diluted by a factor of 10 into distilled water.
14 The operating conditions of the HPLC were as follows:
Column: POROS RH 2.1 mm x 3.0 cm 16 Mobile phase: A: 95% H2O, 0.1 % TFA, 5% ACN
17 B: 95% ACN, 5% H2O, 0.083% TFA
18 Gradient: 20% B to 50% B in 5 minutes 19 Flow: 2.0 ml/min Detector: 280 nm @ 0.002 AUFS
21 IRMA Standards: Working standards were prepared by diluting IRMA
22 standards into phosphate buffered saline (PBS) containing 0.5% Bovine 23 Serum Albumin (BSA). Samples were prepared by serially diluting by factors 24 of 400 for interferon formulations and 2000 for the standard into PBS
containing 0.5% BSA.
26 Figure 3 shows the results of the HPLC and the IRMA assays.
27 The HPLC measurements indicate no losses of the a-IFN over 5 days, even 28 at 37 C, indicating stability of this protein in non-aqueous vehicle.
Relative 29 to the initial stock solution, the activity shown by IRMA at t = 0 is 78%.
*Trade-mark 1 At t = 5 days, the formulation displayed an activity of 87% at room 2 temperature and 90% at 37 C. When compared to the original stock, 3 no losses of a-IFN were detected by HPLC in this formulation. Stability 4 of interferon in PEG over 5 days at 37 C was indicated by this assay. =
However, approximately 80 - 90% of the activity of the initial stock was 6 maintained. The IRMA readings suggest no activity losses due to time and 7 temperature effects.
8 This invention has been described in detail with particular reference 9 to certain preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of 11 the invention.
Claims (21)
1. A beneficial agent formulation for use in a device which delivers the formulation over an extended delivery period, the formulation comprising a suspension containing at least 5% by weight beneficial agent in the form of solid particles, the beneficial agent particle size being 0.3 to 50 microns and the suspension viscosity being sufficient to prevent settling of the agent in the suspension formulation over the extended delivery period.
2. The formulation of claim 1, wherein the particle size is between 1 to 10 microns.
3. The formulation of claim 1 or 2, wherein the viscosity is 100 to 100,000 poise at 37°C.
4. The formulation of claim 1, 2 or 3, wherein the extended delivery period is at least about 1 week.
5. The formulation of claim 1, 2 or 3, wherein the extended delivery period is at least about 1 month.
6. The formulation of any one of claims 1 to 5, wherein the liquid suspension further comprises a low molecular weight polyol and a thickening agent.
7. The formulation of claim 6, wherein the polyol is polyethylene glycol having a molecular weight between 200 and 1000.
8. The formulation of claim 6, wherein the polyol is polyethylene glycol having a molecular weight between 200 and 600.
9. The formulation of claim 6, 7 or 8, wherein the thickening agent comprises povidone.
10. The formulation of claim 6, 7 or 8, wherein the thickening agent comprises hydroxypropyl cellulose.
11. The formulation of any one of claims 1 to 10, wherein the beneficial agent is human .alpha.-interferon.
12. The formulation of claim 11, wherein the concentration of interferon is at least 1 x 10 9 IU.
13. The formulation of any one of claims 1 to 10, wherein said beneficial agent is a water sensitive compound.
14. A beneficial agent delivery device containing the formulation of any one of claims 1 to 13.
15. The beneficial agent delivery device of claim 14, wherein the device is adapted to be implanted within an animal.
16. A composition for sustained controlled delivery over an extended delivery period, the composition comprising:
(a) 0.5% to 70% by weight beneficial agent having a particle size of between 0.3 to 50 microns; and (b) a non-aqueous liquid suspension formulation characterized by a viscosity of between 100 to 100,000 poise at 37°C, the formulation further comprising polyethylene glycol with a molecular weight between 200 and 1000 and a thickening agent.
(a) 0.5% to 70% by weight beneficial agent having a particle size of between 0.3 to 50 microns; and (b) a non-aqueous liquid suspension formulation characterized by a viscosity of between 100 to 100,000 poise at 37°C, the formulation further comprising polyethylene glycol with a molecular weight between 200 and 1000 and a thickening agent.
17. The composition according to claim 16, wherein the thickening agent comprises povidone or hydroxypropyl cellulose.
18. The composition of claim 16 or 17, wherein the extended delivery period is at least about 1 week.
19. The composition of claim 16 or 17, wherein the extended delivery period is at least about 1 month.
20. A beneficial agent delivery device containing the composition of claim 16 or 17.
21. The beneficial agent delivery device of claim 20, wherein the device is adapted to be implanted within an animal.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/475,238 | 1995-06-07 | ||
| US08/475,238 US5904935A (en) | 1995-06-07 | 1995-06-07 | Peptide/protein suspending formulations |
| PCT/US1996/007377 WO1996040049A1 (en) | 1995-06-07 | 1996-05-22 | Peptide/protein suspended formulations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2220871A1 CA2220871A1 (en) | 1996-12-19 |
| CA2220871C true CA2220871C (en) | 2011-02-08 |
Family
ID=23886776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2220871A Expired - Fee Related CA2220871C (en) | 1995-06-07 | 1996-05-22 | Peptide/protein suspending formulations |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US5904935A (en) |
| EP (1) | EP0831773B1 (en) |
| JP (2) | JPH11506730A (en) |
| KR (1) | KR100460653B1 (en) |
| CN (1) | CN1138528C (en) |
| AT (1) | ATE187062T1 (en) |
| AU (1) | AU706318B2 (en) |
| CA (1) | CA2220871C (en) |
| DE (1) | DE69605417T2 (en) |
| DK (1) | DK0831773T3 (en) |
| ES (1) | ES2139360T3 (en) |
| FI (1) | FI119464B (en) |
| NZ (1) | NZ308843A (en) |
| WO (1) | WO1996040049A1 (en) |
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- 1995-06-07 US US08/475,238 patent/US5904935A/en not_active Expired - Lifetime
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1996
- 1996-05-22 DE DE69605417T patent/DE69605417T2/en not_active Expired - Lifetime
- 1996-05-22 CN CNB961944943A patent/CN1138528C/en not_active Expired - Fee Related
- 1996-05-22 EP EP96920358A patent/EP0831773B1/en not_active Expired - Lifetime
- 1996-05-22 ES ES96920358T patent/ES2139360T3/en not_active Expired - Lifetime
- 1996-05-22 AT AT96920358T patent/ATE187062T1/en not_active IP Right Cessation
- 1996-05-22 DK DK96920358T patent/DK0831773T3/en active
- 1996-05-22 KR KR1019970708967A patent/KR100460653B1/en not_active IP Right Cessation
- 1996-05-22 AU AU58694/96A patent/AU706318B2/en not_active Ceased
- 1996-05-22 NZ NZ308843A patent/NZ308843A/en not_active IP Right Cessation
- 1996-05-22 CA CA2220871A patent/CA2220871C/en not_active Expired - Fee Related
- 1996-05-22 JP JP9500644A patent/JPH11506730A/en not_active Withdrawn
- 1996-05-22 WO PCT/US1996/007377 patent/WO1996040049A1/en active IP Right Grant
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1997
- 1997-12-05 FI FI974429A patent/FI119464B/en active IP Right Grant
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1999
- 1999-01-28 US US09/238,159 patent/US5972370A/en not_active Expired - Lifetime
-
2008
- 2008-10-22 JP JP2008271657A patent/JP2009057389A/en active Pending
Also Published As
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|---|---|
| DK0831773T3 (en) | 2000-05-08 |
| JP2009057389A (en) | 2009-03-19 |
| US5904935A (en) | 1999-05-18 |
| ATE187062T1 (en) | 1999-12-15 |
| DE69605417D1 (en) | 2000-01-05 |
| FI974429A0 (en) | 1997-12-05 |
| WO1996040049A1 (en) | 1996-12-19 |
| ES2139360T3 (en) | 2000-02-01 |
| DE69605417T2 (en) | 2000-03-23 |
| JPH11506730A (en) | 1999-06-15 |
| CN1187119A (en) | 1998-07-08 |
| KR19990022486A (en) | 1999-03-25 |
| AU5869496A (en) | 1996-12-30 |
| EP0831773A1 (en) | 1998-04-01 |
| CN1138528C (en) | 2004-02-18 |
| FI974429A (en) | 1997-12-05 |
| AU706318B2 (en) | 1999-06-17 |
| KR100460653B1 (en) | 2005-08-05 |
| FI119464B (en) | 2008-11-28 |
| EP0831773B1 (en) | 1999-12-01 |
| US5972370A (en) | 1999-10-26 |
| NZ308843A (en) | 2000-01-28 |
| CA2220871A1 (en) | 1996-12-19 |
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| EEER | Examination request | ||
| MKLA | Lapsed |
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