Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS20020115588 A1
Publication typeApplication
Application numberUS 09/383,590
Publication dateAug 22, 2002
Filing dateAug 26, 1999
Priority dateDec 22, 1994
Also published asCA2206657A1, CA2206657C, CN1170361A, CN1170527C, DE69530519D1, DE69530519T2, EP0806945A1, EP0806945B1, EP1283035A2, EP1283035A3, US6436902, US20030064928, WO1996019206A1
Publication number09383590, 383590, US 2002/0115588 A1, US 2002/115588 A1, US 20020115588 A1, US 20020115588A1, US 2002115588 A1, US 2002115588A1, US-A1-20020115588, US-A1-2002115588, US2002/0115588A1, US2002/115588A1, US20020115588 A1, US20020115588A1, US2002115588 A1, US2002115588A1
InventorsKjell Backstrom, Bjorn Wallmark, Magnus Dahlback, Peter Edman, Ann Johansson
Original AssigneeKjell Backstrom, Bjorn Wallmark, Magnus Dahlback, Peter Edman, Ann Johansson
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Dry powder of parathyroid hormone suitable for inhalation of specified particle size in diameters; treating osteoporosis
US 20020115588 A1
Abstract
The present invention relates to compositions and methods for pulmonary administration of full-length parathyroid hormone to mammalian hosts for the treatment of osteoporosis. Thus there is provided a therapeutic preparation comprising a human full-length parathyroid hormone, or homologues thereof, in the form of a dry powder suitable for inhalation in which at least 50% of said dry powder consists of (a) particles having a diameter of up to 10 microns; or (b) agglomerates of such particles.
Images(1)
Previous page
Next page
Claims(29)
1. A therapeutic preparation for delivery from a dry powder inhaler device comprising active substance or substances (i) a parathyroid hormone (PTH), and optionally (ii) a substance which enhances the absorption of PTH in the lower respiratory tract, said active substance or substances being in the form of a dry powder suitable for inhalation in which at least 50% of said dry powder consists of primary particles having a diameter of up to 10 microns.
2. A therapeutic preparation according to claim 1, characterized in that the dry powder further comprises a pharmaceutically acceptable carrier.
3. A therapeutic preparation according to claim 2, characterized in that said carrier consists of particles having a diameter of up to 10 microns such that at least 50% of said dry powder consists of (a) primary particles having a diameter of up to 10 microns; or (b) agglomerates of such primary particles.
4. A therapeutic preparation according to claim 3, in which at least 50% of the dry powder consists of (a) primary particles having a diameter of between 1 and 6 microns or (b) agglomerates of such primary particles.
5. A therapeutic preparation according to claim 2, characterised in that said carrier consists of coarse particles, such that an ordered mixture may be formed between said active compounds and the carrier.
6. A therapeutic preparation according to claim 1 or claim 5, in which at least 50% of the total mass of parathyroid hormone consists of primary particles having a diameter of between 1 and 6 microns.
7. A therapeutic preparation according to claim 1, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
8. A therapeutic preparation according to claim 7, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises amino acids 1-84 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
9. A therapeutic preparation according to claim 2, characterised in that the carrier is selected from mono-, di-, and polysaccharides, sugar alcohols and other polyols.
10. A therapeutic preparation according to claim 2, characterised in that the carrier is lactose.
11. A therapeutic preparation according to claim 2, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
12. A therapeutic preparation according to claim 3, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
13. A therapeutic preparation according to claim 4, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
14. A therapeutic preparation according to claim 5, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
15. A therapeutic preparation according to claim 6, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 34 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
16. A therapeutic preparation according to claim 3, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 84 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
16. A therapeutic preparation according to claim 4, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 84 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
18. A therapeutic preparation according to claim 5, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 84 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
19. A therapeutic preparation according to claim 6, characterized in that the parathyroid hormone is a human parathyroid hormone which comprises at least amino acids 1 to 84 of the sequence shown as SEQ ID NO:1 in the Sequence Listing.
20. The therapeutic preparation of claim 1, comprising a salt of a fatty acid, wherein the salt of the fatty acid enhances the absorption of PTH in the lower respiratory tract.
21. The therapeutic preparation of claim 20, wherein the salt of a fatty acid is sodium caprate.
22. The therapeutic preparation of claim 1, comprising a bile salt or derivative thereof, wherein the bile salt or derivative thereof enhances the absorption of PTH in the lower respiratory tract.
23. The therapeutic preparation of claim 22, wherein the bile salt or derivative thereof is sodium taurocholate.
24. The therapeutic preparation of claim 1, comprising a phospholipid, wherein the phospholipid enhances the absorption of PTH in the lower respiratory tract.
25. The therapeutic preparation of claim 1, comprising a cyclodextrin or derivative thereof, wherein the cyclodextrin or derivative thereof enhances the absorption of PTH in the lower respiratory tract.
26. The therapeutic preparation of claim 1, wherein the therapeutic preparation lacks the optional substance which enhances the absorption of PTH in the lower respiratory tract.
27. The therapeutic preparation of claim 1, wherein the primary particles are agglomerated.
28. The therapeutic preparation of claim 1, comprising the substance which enhances the absorption of PTH in the lower respiratory tract.
29. The therapeutic preparation of claim 39, wherein the substance which enhances the absorption of PTH in the lower respiratory tract is selected from the group consisting of a salt of a fatty acid, a phospholipid, a chelator, and a cylcodextrin or derivative thereof.
Description
TECHNICAL FIELD

[0001] The present invention relates to compositions and methods for pulmonary administration of parathyroid hormone (parathormone, PTH) to mammalian hosts for the treatment of osteoporosis.

BACKGROUND ART

[0002] Human parathyroid hormone is an 84 amino acid protein (SEQ ID NO: 1) involved in calcium and phosphorus homeostasis and control of bone growth and density. Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Human PTH is also commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in EP-B-0383751.

[0003] In mammals, the balance between bone formation, associated with the activity of osteoblasts, on one hand, and bone loss, associated with the activity of osteoclasts, on the other hand, is disturbed in several bone affecting diseases, such as osteoporosis. Parathyroid hormone has been shown to have a potential therapeutic role in osteoporosis. The anabolic actions of parathyroid hormone on bone are reviewed in Dempster et al. (1993) Endocrine Reviews, vol. 14, 690-709.

[0004] The N-terminal fragment of human PTH (PTH 1-34) was shown to have an anabolic effect on trabecular bone in involutional osteoporosis by Reeve et al. (1980) British Medical Journal, vol. 280,1340-1344. However, the administration of a wild-type protein is to be preferred when possible, since this will ensure that all biological effects of the natural protein are exerted by the administered compound.

[0005] Polypeptide drugs such as PTH cannot be orally administered in effective doses, since they are rapidly degraded by enzymes in the gastrointestinal tract, and by the low pH in the stomach, before they can reach the bloodstream. Administration of PTH has generally been accomplished subcutaneously by injection. However, injection on a daily basis is inconvenient for the patient. Because of these disadvantages, there is a need for PTH in a form which is administrable other than Dy injection.

[0006] Pulmonary delivery of parathyroid hormone and N-terminal fragments thereof to rats is disclosed in WO 94/07514. When the N-terminal fragment consisting of amino acids 1-34 (PTH34) was administered to rats intratracheally (IT), the serum profile exhibited a peak after 15 minutes with activity diminishing rapidly thereafter. In contrast, the serum profile after IT administration of full-length PTH (PTH84) exhibited a plateau which did not diminish significantly during the 90 minutes of the experiment. Since it is known that PTH is most effectively delivered to a patient in pulsatile fashion, i.e. serum concentrations should rise rapidly after administration and fall rapidly after a peak has been reached, it is concluded in the document WO 94/07514 that N-terminal fragments of PTH is preferred over the full-length protein for pulmonary delivery.

SUMMARY OF THE INVENTIVE CONCEPT

[0007] According to the present invention it has been shown that a pulsative plasma profile is obtained when full-length PTH as a dry powder aerosol is inhaled via an endotracheal tube by dogs. It has thus surprisingly been shown that pulmonary administration of full-length PTH, contrary to the conclusions expressed in the published patent application WO 94/07514, will be effective for stimulating bone formation and for the treatment of osteoporosis.

BRIEF DESCRIPTION OF THE DRAWING

[0008]FIG. 1

[0009] Plasma concentration in dogs after inhalation of PTH 1-34 and PTH 1-84, respectively. ()-▪-) PTH 1-84 (inhaled dose 14 μg/kg); (. . . A . . . ) PTH 1-34 (inhaled dose 4.0 μg/kg).

DISCLOSURE OF THE INVENTION

[0010] In a first aspect of the invention there is provided a therapeutic material, which preferably is a therapeutic preparation, comprising a parathyroid hormone having substantially the biological activities of full-length parathyroid hormone. The said therapeutic material is in the form of a dry powder suitable for inhalation in which at least 50% of the total mass of the active compound PTH consists of (a) primary particles having a diameter of less than about 10 microns, for example between 0.01 and 10 microns, and preferably between 1 and 6 microns, or (b) agglomerates of said particles.

[0011] The therapeutic preparation of the present invention may contain only the said active compound PTH, or it may contain other substances, such as a pharmaceutically acceptable carrier. This carrier may largely consist of particles having a diameter of less than about 10 microns, so that at least 50% of the resultant powder as a whole consists of optionally agglomerated primary particles having a diameter of less than about 10 microns, for example between 0.01 and 10 microns, and preferably between 1 and 6 microns, or (b) agglomerates of said particles.

[0012] Alternatively, the carrier may largely consist of much bigger particles (“coarse particles”), so that an “ordered mixture” may be formed between the active compounds and the said carrier. In an ordered mixture, alternatively known as an interactive or adhesive mixture, fine drug particles (in this invention, the active compounds) are fairly evenly distributed over the surface of coarse excipient particles (in this invention, the pharmaceutically acceptable carrier). Preferably in such case the active compounds are not in the form of agglomerates prior to formation of the ordered mixture. The coarse particles may have a diameter of over 20 microns, such as over 60 microns. Above these lower limits, the diameter of the coarse particles is not of critical importance so various coarse particle sizes may be used, if desired according to the practical requirements of the particular formulation. There is no requirement for the coarse particles in the ordered mixture to be of the same size, but the coarse particles may advantageously be of similar size within the ordered mixture. Preferably, the coarse particles have a diameter of 60-800 microns.

[0013] Preferably at least 60%, such as at least 70% or at least 80%, and more preferably at least 90% of the total mass of the active compound PTH consists of particles having a diameter of less than about 10 microns, or of agglomerates of such particles. When the dry powder preparation comprises carrier, other than when an ordered mixture is desired, preferably at least 60%, such as at least 70% or at least 80%, and more preferably at least 90% by mass of the total dry powder consists of particles having a diameter of less than about 10 microns, or of agglomerates of such particles.

[0014] While the dry powder for inhalation, whether with or without pharmaceutically acceptable carrier, may contain agglomerates of particles as indicated above, at the time of inhalation any agglomerates should be substantially deagglomerated yielding a powder of which at least 50% consists of particles having a diameter of up to 10 microns. The agglomerates can be the result of a controlled agglomeration process or they may simply be the result of the intimate contact of the powder particles. In either case it is essential that the agglomerates are capable of being de-agglomerated e.g. by mechanical means in the inhaler or otherwise, into the aforesaid particles. Agglomerates are in general preferably not formed in the ordered mixture. In the case of an ordered mixture, the active compounds should be released from the large particles preferably upon inhalation, either by mechanical means in the inhaler or simply by the action of inhalation, or by other means, the active compounds then being deposited in the lower respiratory tract and the carrier partides in the mouth.

[0015] When desirable, it will be possible to include in the preparation a substance which enhances the absorption of PTH in the lower respiratory tract. Such a substance can be any of a number of compounds which act to enhance absorption through the layer of epithelial cells lining the alveoli of the lungs and into the adjacent pulmonary vasculature. Examples of enhancers are salts of fatty acids, e.g. sodium caprate, bile salts and derivatives thereof; phospholipids; chelators; and cyclodextrins and derivatives thereof. Additional examples of suitable enhancers can be found in the International Patent Applications WO 95/00127 and WO 95/00128.

[0016] The parathyroid hormone to be used according to the invention is preferably a human parathyroid hormone, although any biologically active form or derivative of PTH, having substantially the biological activities of full-length parathyroid hormone, may be used.

[0017] Preferably, the PTH to be used according to the invention is a parathyroid hormone which comprises at least amino acids 1 to 34, more preferably amino acids 1 to 84, of the sequence shown as SEQ ID NO:1 in the Sequence Listing. However, the PTH to be used according to the invention is not to be limited strictly to PTH having the sequence shown in the Sequence Listing. Rather the invention encompasses use of PTH polypeptides carrying modifications like substitutions, small deletions, insertions or inversions, which polypeptides nevertheless have substantially the biological activities of the full-length PTH which amido acid sequence is disclosed in the Sequence Listing. Included in the invention are consequently also the use of polypeptides, the amino acid sequence of which is at least 90% homologous, preferably at least 95% homologous, with the amino acid sequence shown in the Sequence Listing. Modifications of full-length PTH can be developed in order to improve various properties, for example to improve stability or give an improved pharmacokinetic profile (i.e. improved profile of absorption through the epithelial membranes).

[0018] As stated above, additive substances commonly included in therapeutic preparations, such as pharmaceutically acceptable carriers, may be included in the therapeutic preparation of the present invention. Additive substances may be included for example in order to dilute the powder to an amount which is suitable for delivery from the particular intended powder inhaler; to facilitate the processing of the preparation; to improve the powder properties of the preparation; to improve the stability of the preparation, e.g. by means of antioxidantia or pH-adjusting compounds; or to add a taste to the preparation. Any additive should not adversely affect the stability of PTH, or disadvantageously interfere with absorption of PTH. It should also be stable, not hygroscopic, have good powder properties and have no adverse effects in the airways.

[0019] As examples of potential additives may be mentioned mono-, di-, and polysaccharides, sugar alcohols and other polyols, such as for example lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol and starch. Depending upon the inhaler to be used, the total amount of such additives may vary over a very wide range.

[0020] In some circumstances little or no additive would be required, whereas for example in the case of an inhaler requiring large powder volumes for operation, a very high percentage of the therapeutic preparation could consist of additive. The amount of additive desirable would be easily determined by a person skilled in the art according to particular circumstances.

[0021] A useful mechanism for delivery of the powder according to the invention into the lungs of a patient is through a portable inhaler device suitable for dry powder inhalation. Many such devices, typically designed to deliver antiasthmatic or antiinflammatory agents into the respiratory system, are on the market. Preferably the device is a dry powder inhaler of a design which provides protection of the powder from moisture and has no risk for overdosing, i.e. for occasional large doses. In addition as many as possible of the following characteristics are desired: protection of the powder from light; high respirable fraction and high lung deposition in a broad flow rate interval; low deviation of dose and respirable fraction; low retention of powder in the mouthpiece; low adsorption to the inhaler surfaces; flexibility in dose size; and low inhalation resistance.

[0022] The inhaler is preferably a single dose inhaler although a multi dose inhaler, preferably such as a multi dose, breath actuated, dry powder inhaler for multiple use, may also be employed. A suitable multi dose inhaler is described in EP-B-0069715 and in EP-B-0237507. Preferably the inhaler used is a unit dose, breath actuated, dry powder inhaler for single use. A preferable unit dose inhaler is described in EP-A-0548166 and in EP-A-0558879.

[0023] Consequently, a further aspect of the invention is the use of a therapeutic preparation according to the invention in an inhalation device. Preferably, the said inhalation device provides protection of the powder for inhalation from moisture, and has minimal risk of overdosing. The said inhalation device can be e.g. a unit dose, breath actuated, dry powder inhaler for single usage, or a multi dose, breath actuated, dry powder inhaler for multiple use.

[0024] Yet a further aspect of the invention is a dry powder inhalation device containing the therapeutic preparation as defined above.

[0025] A further important aspect of the invention is a process for the manufacture of a therapeutic preparation as defined above. The described powder preparation can be manufactured in several ways, using conventional techniques. It may be necessary to micronise the active compounds and if appropriate (ie where an ordered mixture is not intended) any carrier in a suitable mill, for example in a jet mill at some point in the process, in order to produce primary particles in a size range appropriate for maximal deposition in the lower respiratory tract (i.e., under 10 μm). For example, one can dry mix PTH and carrier, where appropriate, and then micronise the substances together; alternatively, the substances can be micronised separately, and then mixed. Where the compounds to be mixed have different physical properties such as hardness and brittleness, resistance to micronisation varies and they may require different pressures to be broken down to suitable particle sizes. When micronised together, therefore, the obtained particle size of one of the components may be unsatisfactory. In such case it would be advantageous to micronise the different components separately and then mix them.

[0026] It is also possible first to dissolve the active component including, where an ordered mixture is not intended, any carrier in a suitable solvent, e.g. water, to obtain mixing on the molecular level. This procedure also makes it possible to adjust the pH-value to a desired level. The pharmaceutically accepted limits of pH 3.0 to 8.5 for inhalation products must be taken into account, since products with a pH outside these limits may induce irritation and constriction of the airways. To obtain a powder, the solvent must be removed by a process which retains the biological activity of PTH. Suitable drying methods include vacuum concentration, open drying, spray drying, freeze drying and use of supercritical fluids. Temperatures over 40° C. for more than a few minutes should generally be avoided, as some degradation of the PTH may occur. Following the drying step, the solid material can, if necessary, be ground to obtain a coarse powder, then, if necessary, micronised.

[0027] If desired, the micronised powder can be processed to improve the flow properties, e.g., by dry granulation to form spherical agglomerates with superior handling characteristics, before it is incorporated into the intended inhaler device. In such a case, the device would be configured to ensure that the agglomerates are substantially deagglomerated prior to exiting the device, so that the particles entering the respiratory tract of the patient are largely within the desired size range.

[0028] Where an ordered mixture is desired, the active compound may be processed, for example by micronisation, in order to obtain, if desired, particles within a particular size range. The carrier may also be processed, for example to obtain a desired size and desirable surface properties, such as a particular surface to weight ratio, or a certain ruggedness, and to ensure optimal adhesion forces in the ordered mixture. Such physical requirements of an ordered mixture are well known, as are the various means of obtaining an ordered mixture which fulfils the said requirements, and may be determined easily by the skilled person according to the particular circumstances.

[0029] Yet a further aspect of the invention is a method for the treatment of osteoporosis comprising administering, to a patient in need thereof, an effective amount of a therapeutic preparation as defined above. Suitable doses can be in the range of 1 to 100 μg full-length PTH/kg, e.g. around 30 μg/kg.

[0030] The invention will now be described by way of Examples, which are intended to illustrate but not limit the scope of the invention.

EXAMPLES Example 1

[0031] 1.1. Therapeutic Preparation of PTH 1-84 for Inhalation

[0032] An aqueous solution with the following composition is made:

Human PTH 1-84 41 mg
Citric acid, monohydrate 57 mg
Sodium citrate 113 mg
Lactose 3888 mg
Water approx. 53 ml

[0033] The pH is adjusted to 5.0. The solution is concentrated by evaporation, at a temperature of 37° C., over a period of about one day. The obtained solid cake is crushed and sieved through a 0.5 mm sieve, and the resultant powder micronised through a jet mill to particles of about 2 microns in diameter.

[0034] 1.2. Therapeutic Preparation of PTH 1-34 for Inhalation

[0035] An aqueous solution with the following composition is made:

Human PTH 1-34 11.2 mg
Citric acid, monohydrate 66 mg
Sodium citrate 131 mg
Lactose 4589 mg
Water approx. 52 ml

[0036] The solution is further treated as described in Example 1.1. above.

[0037] 1.3. Therapeutic PTH Preparation Including an Enhancer

[0038] An aqueous solution with the following composition is made:

Human PTH 1-84 50 mg
Citric acid, monohydrate 69 mg
Sodium citrate 138 mg
Sodium taurocholate 17 mg
Lactose 4726 mg
Water approx. 60 ml

[0039] The pH is adjusted to 5.0. The solution is concentrated by evaporation, at a temperature of 37° C., over a period of about one day. The obtained solid cake is crushed and sieved through a 0.5 mm sieve, and the resultant powder micronised through a jet mill to particles of about 2 microns in diameter.

Example 2

[0040] Pharmacokinetic Studies

[0041] 2.1. Powder Formulation and Inhalation System

[0042] Human PTH 1-84 or PTH 1-34 were prepared according to Examples 1.1 and 1.3, respectively. The powder formulations were compressed in dust containers and generated continuously as dry powder aerosols by a Wright Dust Feed (WDF). The aerosols were generated by scraping off the formulations from the tablets in the dust containers. The mass flow through the WDF was 8.01 /min.

[0043] The inhaled dose (ID) was determined by measuring the inspiratory tidal volume (ITV) and the PTH concentration during inhalation.

[0044] 2.2. Treatment

[0045] Beagle dogs (n=5, at each formulation) were starved for 16 hours before inhalation and the experiments were performed in the mornings. The dogs were anaesthetized with Plegecil® and Penthotal®, intubated and exposed with either PTH 1-34 or PTH 1-84 for about 10 minutes.

[0046] Venous blood samples for determination of PTH concentration were taken from the jugular vein into heparinized vacutainer tubes (2 ml). The samples were collected before dosing and at 10, 15, 20, 30, 40, 60, 90, 120, 240 and 360 minutes after start (t=0) of inhalation. The whole blood samples were centrifuged immediately, alternatively kept in ice water for maximum 20 minutes before centrifugation, and the plasma (1 ml) was sampled for PTH analysis. PTH in plasma was analyzed using radioimmununoassay (RIA) kits.

[0047] The results (Table 1 and FIG. 1) clearly show that inhalation of both PTH 1-34 and PTH 1-84 results in a pulsatile serum profile similar to that obtained with subcutaneous administration of PTH, confirming that pulmonary administration of full-length PTH, or a PTH fragment having substantially the biological activities of full-length PTH, will be effective for stimulating bone formation and for the treatment of osteoporosis.

Example 3

[0048] Bone Effect

[0049] The bone effect is measured in ovariectomized osteopenic rats as mineral density as weight/volume of the distal femur after 4 weeks of administration; starting 6 weeks post ovariectomy. The obtained results show that inhalation of full-length PTH has a significant effect on femur bone formation.

TABLE 1
Plasma concentration of PTH in dogs after inhalation of PTH 1-34 or
PTH 1-84
PTH 1-34 PTH 1-84
Time Conc. Conc.
(min) (pM) S.E. (pM) S.E.
 0 8.0 1.82 3.4 1.02
10 30.4 4.99 8.3 1.04
15 47.4 5.20 11.4 1.01
20 49.6 6.81 11.6 1.11
30 44.6 8.55 9.6 1.15
40 36.2 6.84 7.9 1.21
60 26.0 4.90 5.8 0.84
90 17.0 2.05 4.1 0.60
120  12.6 2.06 3.0 0.36
240  6.0 1.76 2.2 0.40
360  7.6 2.93 2.6 0.85

Classifications
U.S. Classification424/499, 514/44.00R
International ClassificationA61K9/14, A61K9/72, A61P43/00, A61P19/10, A61K38/22, A61K47/12, A61K38/29, A61K9/00
Cooperative ClassificationY10S514/826, A61K47/12, A61K9/0075, A61K38/29
European ClassificationA61K47/12, A61K38/29, A61K9/00M20B3
Legal Events
DateCodeEventDescription
Oct 7, 2014FPExpired due to failure to pay maintenance fee
Effective date: 20140820
Aug 20, 2014LAPSLapse for failure to pay maintenance fees
Mar 28, 2014REMIMaintenance fee reminder mailed
Jan 22, 2010FPAYFee payment
Year of fee payment: 8
Dec 28, 2005FPAYFee payment
Year of fee payment: 4
Feb 1, 2005CCCertificate of correction
Apr 15, 2003CCCertificate of correction
Feb 5, 2001ASAssignment
Owner name: ASTRAZENECA AB, SWEDEN
Free format text: CERTIFICATE OF RIGISTRATION;ASSIGNOR:ASTRA AKTIEBOLAG;REEL/FRAME:011505/0723
Effective date: 20000113
Owner name: ASTRAZENECA AB S-151 85 SODERTALJE SWEDEN
Owner name: ASTRAZENECA ABS-151 85 SODERTALJE, (1) /AE
Free format text: CERTIFICATE OF RIGISTRATION;ASSIGNOR:ASTRA AKTIEBOLAG /AR;REEL/FRAME:011505/0723
Nov 22, 1999ASAssignment
Owner name: ASTRA AKTIEBOLAG, SWEDEN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DAHLBACK, MAGNUS;EDMAN, PETER;JOHANSSON, ANN;REEL/FRAME:010408/0200;SIGNING DATES FROM 19990922 TO 19990924
Owner name: ASTRA AKTIEBOLAG S-151 85 SODERTALJE SWEDEN