Patent Grant
7074430
The present invention relates to a controlled release preparation for oral administration, to processes for its preparation and to its medical use. In particular, the invention relates to a controlled release preparation comprising tramadol or a pharmaceutically acceptable salt thereof.
Tramadol, which has the chemical name (±)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, is an orally active opioid analgesic. Conventional release preparations in the form of capsules, drops and suppositories containing tramadol, or more particularly its hydrochloride salt, have been commercially available for many years for use in the treatment of moderate to severe pain; Such preparations, however, do not provide a controlled release of the tramadol. Moreover, despite tramadol's long-standing use, controlled release preparations for oral administration containing tramadol as active ingredient have not even previously been described in the literature.
It is an object of the present invention to provide an oral controlled release tramadol preparation suitable for at least twelve-hourly (e.g. up to twenty-four hourly) administration for the treatment of pain.
The present invention therefore provides a controlled release preparation comprising tramadol or a pharmaceutically acceptable salt thereof for oral administration.
Suitable pharmaceutically acceptable salts of tramadol for use according to the present invention are those conventionally known in the art such as pharmaceutically acceptable acid addition salts. The hydrochloride salt is particularly preferred.
A controlled release preparation according to the present invention is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
The present inventors have found that in order to allow for controlled release tramadol over at least a twelve hour-period following oral administration, the in vitro release rate preferably corresponds to the following % rate of tramadol released:
Another preferred preparation especially suited for twice-a-day dosing has an in vitro release rate corresponding to the following % rate of tramadol released:
Yet another preferred preparation particularly suited for once-a-day dosing has an in-vitro release rate corresponding to the following % rate of tramadol released:
A still further preferred preparation in accordance with the invention also particularly suited for once-a-day dosing has an in vitro release rate corresponding to the following % rate of tramadol released.
More preferably a preparation for once-a-day dosing has an in vitro release rate substantially as follows:
Another preferred dissolution rate in vitro upon release of the controlled release preparation twice daily according to the invention, is between 5 and 50% (by weight) tramadol released after 1 hour, between 10 and 75% (by weight) tramadol released after 2 hours, between 20 and 95% (by weight) tramadol released after 4 hours, between 40 and 100% (by weight) tramadol released after 8 hours, more than 50% (by weight) tramadol released after 12 hours, more than 70% (by weight) released after 18 hours and more than 80% (by weight) tramadol released after 24 hours.
Furthermore, it is preferred in the case of a controlled release preparation for administration twice daily that after 8 hours following oral administration between 70 and 95% (by weight) tramadol is absorbed in vivo, between 77 and 97% (by weight) tramadol is absorbed after 10 hours and between 80 and 100% (by weight) tramadol is absorbed after 12 hours.
A formulation in accordance with the invention suitable for twice-a-day dosing may have a tmax of 1.5 to 8 hours, preferably 2 to 7 hours, and a W50 value in the range 7 to 16 hours.
A formulation in accordance with the invention suitable for once-a-day dosing may have a tmax in the range of 3 to 6 hours, preferably 4 to 5 hours and a W50 value in the range of 10 to 33 hours.
The W50 parameter defines the width of the plasma profile at 50% Cmax, i.e. the duration over which the plasma concentrations are equal to or greater than 50% of the peak concentration. The parameter is determined by linear interpolation of the observed data and represents the difference in time between the first (or only) upslope crossing and the last (or only) downslope crossing in the plasma profile.
The in vitro release rates mentioned herein are, except where otherwise specified, those obtained by measurement using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37° C. and using UV detection at 270 nm.
The in viva absorption rate is determined from measurement of plasma concentration against time using the deconvolution techniqiue. A conventional release tramadol drop preparation (Tramal (trade mark), Grunenthal) was used as the weighting-function and the elimination half life of tramadol was taken as 7.8 hours.
The controlled release preparation according to the invention preferably contains an analgesically effective amount of tramadol or a pharmaceutically acceptable salt thereof, conveniently in the range of from 50 to 800 mg, especially 100, 200, 300, 400 to 600 mg (calculated as tramadol hydrochloride) per dosage unit.
The controlled release preparation according to the invention may be presented, for example, as granules, spheroids, pellets, multiparticulates, capsules, tablets, sachets, controlled release suspensions, or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates.
The active ingredient in the preparation according to the invention may suitably be incorporated in a matrix. This may be any matrix that affords controlled release tramadol over at least a twelve hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of tramadol within the ranges specified above. Preferably the matrix is a controlled release matrix. Alternatively, normal release matrices having a coating which provides for controlled release of the active ingredient may be used.
Suitable materials for inclusion in a controlled release matrix include
One particularly suitable controlled release matrix comprises one or more alkylcelluloses and one or more C12–C36 aliphatic alcohols. The alkylcellulose is preferably C1–C6 alkyl cellulose, especially ethyl cellulose. The controlled release preparation according to the invention preferably contains from 1 to 20% (by weight), especially from 2 to 15% (by weight) of one or more alkylcelluloses.
The aliphatic alcohol may conveniently be lauryl alcohol, myristyl alcohol or stearyl alcohol but is preferably cetyl alcohol or more preferably cetostearyl alcohol. The controlled release preparation suitably contains from 5 to 30% (by weight) of aliphatic alcohol, especially from 10 to 25% (by weight) of aliphatic alcohol.
Optionally the controlled release matrix may also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colourants, flavourants, surfactants, pH adjusters, anti-adherents and glidants, e.g. dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica.
The controlled release preparation according to the invention may conveniently be film coated using any film coating material conventional in the pharmaceutical art. Preferably an aqueous film coating is used.
Alternatively, the controlled release preparation according to the invention may comprise a normal release matrix having a controlled release coating. Preferably the preparation comprises film coated spheroids containing the active ingredient and a spheronising agent.
The spheronising agent may be any suitable pharmaceutically acceptable material which may be spheronised together with the active ingredient to form spheroids. A preferred spheronising agent is microcrystalline cellulose. The microcrystalline cellulose used may suitably be, for example, Avicel PII 101 or Avicel PII 102 (Trade Marks, FMC Corporation).
Optionally the spheroids may contain other pharmaceutically acceptable ingredients conventional in the pharmaceutical art such as binders, bulking agents and colourants. Suitable binders include water soluble polymers, water soluble hydroxyalkyl celluloses such as hydroxypropylcellulose or water insoluble polymers (which may also contribute controlled release properties) such as acrylic polymers or copolymers for example ethylcellulose. Suitable bulking agents include lactose.
The spheroids are coated with a material which permits release of the active ingredient at a controlled rate in an aqueous medium. Suitable controlled release coating materials include water insoluble waxes and polymers such as polymethacrylates (for example Eudragit polymers, Trade Mark) or water insoluble celluloses, particularly ethylcellulose. Optionally, water soluble polymers such as polyvinylpyrrolidone or water soluble celluloses such as hydroxypropylmethylcellulose or hydroxypropylcellulose may be included. Optionally other water soluble agents such as polysorbate 80 may be added.
Alternatively the drug may be coated onto inert non-pareil beads and the drug loaded beads coated with a material which permits control of the release of the active ingredient into the aqueous medium.
In a further aspect the present invention provides a process for preparing a controlled release preparation according to the present invention comprising incorporating tramadol or a pharmaceutically acceptable salt thereof in a controlled release matrix, for example by
The controlled release preparation according to the invention may also be prepared in the form of film coated spheroids by
One preferred form of unit dose form in accordance with the invention comprises a capsule filled with controlled release particles essentially comprising the active ingredient, a hydrophobic fusible carrier or diluent and optionally a hydrophillic release modifier. In particular, the controlled release particles are preferably prepared by a process which comprises forming a mixture of dry active ingredient and fusible release control materials followed by mechanically working the mixture in a high speed mixer with an energy input sufficient to melt or soften the fusible material whereby it forms particles with the active ingredient. The resultant particles, after cooling, are suitably sieved to give particles having a size range from 0.1 to 3.0 mm, preferably 0.25 to 2.0 mm. An example according to the invention is described below which is suitable for the commercial production of dosage units.
When using such a processing technique it has been found that, in order most readily to achieve the desired release characteristics (both in vivo and in vitro as discussed above) the composition to be processed should comprises two essential ingredients namely:
We have found that the total amount of tramadol or pharmaceutically acceptable salt thereof in the composition may vary within wide limits, for example from 10 to 90% by weight thereof.
The hydrophobic fusible component (b) should be a hydrophobic material such as a natural or synthetic wax or oil, for example hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, Beeswax, Carnauba wax or glyceryl monostearate, and suitably has a melting point of from 35 to 140° C., preferably 45 to 110° C.
The release modifying component (c), when a water soluble fusible material, is conveniently a polyethylene glycol and, when a particulate material, is conveniently a pharmaceutically acceptable material such as dicalcium phosphate or lactose.
Another preferred process for the manufacture of a formulation in accordance with the invention comprises
This process is capable of giving a high yield (over 80%) of particles in a desired size range, with a desired uniformity of release rate of tramadol or salt thereof.
The resulting particles may be sieved to eliminate any over-or undersized material then formed into the desired dosage units by for example, encapsulation into hard gelatin capsules containing the required dose of the active substance or by compression into tablets.
In this method in accordance with the invention preferaby all the tramadol or salt thereof is added in step (a) together with a major portion of the hydrophobic fusible release control material used. Preferably the amount of fusible release control material added in step (a) is between 10% and 90% w/w of the total amount of ingredients added in the entire manufacturing operation, more preferably between 20% and 70% w/w.
Stage (a) of the process may be carried out in conventional high speed mixers with a standard stainless steel interior, e.g. a Collette Vactron 75 or equivalent mixer. The mixture is processed until a bed temperature about 40° C. or above is achieved and the resulting mixture acquires a cohesive granular texture, with particle sizes ranging from about 1–3 mm to fine powder in the case of non-aggregated original material. Such material, in the case of the embodiments described below, has the appearance of agglomerates which upon cooling below 40° C. have structural integrity and resistance to crushing between the fingers. At this stage the agglomerates are of an irregular size, shape and appearance.
The agglomerates are preferably allowed to cool. The temperature to which it cools is not critical and a temperature in the range room temperature to 37° C. may be conveniently used.
The agglomerates are broken down by any suitable means, which will comminute oversize agglomerates and produce a mixture of powder and small particles preferably with a diameter under 2 mm. It is currently preferred to carry out the classification using a Jackson Crockatt granulator using a suitable sized mesh, or a Comil with an appropriate sized screen. We have found that if too small a mesh size is used in the aforementioned apparatus the agglomerates melting under the action of the beater or impeller will clog the mesh and prevent further throughput of mixture, thus reducing yield. A mesh size of 12 has been found adequate.
The classified material is returned to the high speed mixer and processing continued. It is believed that this leads to cementation of the finer particles into particles of uniform size range.
In one preferred form of the method of the invention processing of the classified materials is continued, until the hydrophobic fusible materials used begin to soften/melt and optionally additional hydrophobic fusible material is then added. Mixing is continued until the mixture has been transformed into particles of the desired predetermined size range.
In order to ensure uniform energy input into the ingredients in the high speed mixer it is preferred to supply at least part of the energy by means of microwave energy.
Energy may also be delivered through other means such as by a heating jacket or via the mixer impeller and chopper blades.
After the particles have been formed they are cooled or allowed to cool, and may then be sieved to remove any over or undersized material.
The resulting particles may be used to prepare dosage units in accordance with the invention in the form of e.g. tablets or capsules in manners known per se.
We have also found that particles containing tramadol or a salt thereof produced by a melt processing as described in application PCT/SE93/00225 and the process described and claimed in our prior unpublished UK application No. 9324045.5 filed on 23 Nov. 1993 as well as the process described herein are particularly useful for processing into the form of tablets.
We have found that by suitable selection of the materials used in forming the particles and in the tabletting and the proportions in which they are used, enables a significant degree of control in the ultimate dissolution and release rates of the tramadol or salt thereof from the compressed tablets.
Usually, to form a tablet in accordance with the invention, particles prepared as described above will be admixed with tabletting excipients e.g. one or more of the standard excipients such as diluents, lubricants, binding agents, flow aids, disintegrating agents, surface active agents or water soluble polymeric materials.
Suitable diluents are e.g. microcrystalline cellulose, lactose and dicalcium phosphate. Suitable lubricants are e.g. magnesium stearate and sodium stearyl fumarate. Suitable binding agents are e.g. hydroxypropyl methyl cellulose, polyvidone and methyl cellulose.
Suitable disintegrating agents are starch, sodium starch glycolate, crospovidone and croscarmalose sodium.
Suitable surface active are Poloxamer 188®, polysorbate 80 and sodium lauryl sulfate.
Suitable flow aids are talc colloidal anhydrous silica.
Suitable water soluble polymers are PEG with molecular weights in the range 1000 to 6000.
To produce tablets in accordance with the invention, particles produced in accordance with the invention may be mixed or blended with the desired excipient(s), if any, using conventional procedures, e.g. using a Y-Cone or bin-blender and the resulting mixture compressed according to conventional tabletting procedure using a suitable size tabletting mould. Tablets can be produced using conventional tabletting machines, and in the embodiments described below were produced on standard single punch F3 Manesty machine or Kilian RLE15 rotary tablet machine.
Generally speaking we find that even with such a highly water soluble active agent as tramadol or salt thereof tablets formed by compression according to standard methods give very low release rates of the active ingredient e.g. corresponding to release over a period of greater than 24 hours, say more than 36. We have found that the release profile can be adjusted in a number of ways. For instance a higher loading of the drug will be associated with increased release rates; the use of larger proportions of the water soluble fusible material in the particles or surface active agent in the tabletting formulation will also be associated with a higher release rate of the active ingredient. By controlling the relative amounts of these ingredients it is possible to adjust the release profile of the tramadol or salt thereof.
In order that the invention may be well understood the following examples are given by way of illustration only.
The present invention is further illustrated with the accompanying drawings in which:
Tablets having the following formulation were prepared:
Tramadol hydrochloride (100 mg) and lactose (68 mg) were granulated, transferred to a fluid bed granulator and sprayed with ethylcellulose (15 mg) and water. The granules were then dried at 60° C. and passed through a 1 mm screen.
To the warmed tramadol containing granules was added molten cetostearyl alcohol (42 mg) and the whole was mixed thoroughly. The granules were allowed to cool and sieved through a 1.6 mm screen. Purified talc and magnesium stearate were added and mixed with the granules. The granules were then compressed into tablets.
The tablets were coated with a film coat having the formulation given below.
Tablets having the following formulation were prepared:
A mixture of tramadol hydrochloride (100 mg), lactose (58 mg) and ethylcellulose (15 mg) was granulated whilst adding molten cetostearyl alcohol (52 mg) and the whole was mixed thoroughly. The granules were allowed to cool and sieved through a 1.6 mm screen. Purified talc and magnesium stearate were added and mixed with the granules. The granules were then compressed into tablets which were coated with a film coat having the formulation given in Example 1.
Film coated tablets were produced following the procedure described in Example 2 and having the following formulation:
In Vitro Dissolution Studies
In vitro dissolution studies were conducted on tablets prepared as described above. Results are given in Table 1.
In a trial involving 12 healthy volunteers the serum levels of tramadol following administration of one tablet according to Example 2 was found to be as illustrated in
Particles having the formulations given in Table II below were prepared by the steps of:
Samples of the particles from Example 4 were blended with magnesium stearate and purified talc using a Y-Cone or bin-blender. The blended mixture was then compressed using either (1) 14×6 mm, (2) 16×7 mm or (3) 18.6×7.5 mm capsule shaped tooling on a single punch F3 Manesty tabletting machine to give tablets giving 200, 300 and 400 mg of tramadol HCl. The ingredients per dosage unit amounted to the following:
The tablets were assessed by the dissolution using Ph. Eur. Paddle Method 100 rpm, 0.1 N HCl.
To assess the non-compressed particles the Ph Eur. Paddle was replaced by a modified Ph Eur. Basket.
The results are shown in Table IV below;
These results confirm the effectiveness of the tabletting in reducing the release rate.
Samples of the particles from Example 5 were then tabletted using a procedure similar to Example 3 and the ingredients per unit dosage amounted to:
The tablets and samples of non-compressed multiparticulates (each sample containing 400 mg of tramadol hydrochloride) were assessed by the dissolution method also described above. The results are shown in Table VI below;
These results show that by increasing the loading of the highly water soluble tramadol hydrochloride (75% w/w in this example compared with 50% w/w in Example 6) a significantly faster release rate of the active ingredient can be achieved.
Example 4 was repeated but with the following formulation:
The resulting multiparticulates were blended as described in Example 6 with the following;
The blend was then compressed as described in Example 6 but using 15 mm×6.5 mm normal concave capsule shaped plain/plain punches.
The resulting tablets were then assessed by the dissolution method described above. The results are shown in Table V.
In a trial involving five healthy male volunteers the plasma profile resulting from single dose administrations of the above tablet are shown in
This application is a continuation of U.S. patent application Ser. No. 08/677,798, filed Jul. 10, 1996; now U.S. Pat. No. 6,254,887 which is a continuation of U.S. patent application Ser. No. 08/241,129, filed May 10, 1994 (now U.S. Pat. No. 5,591,452).
| Number | Name | Date | Kind |
|---|---|---|---|
| 2738303 | Blythe et al. | Mar 1956 | A |
| 3065143 | Christenson et al. | Nov 1962 | A |
| 3652589 | Flick et al. | Mar 1972 | A |
| 3830934 | Flick et al. | Aug 1974 | A |
| 3845770 | Theeuwes et al. | Nov 1974 | A |
| 3950508 | Mony et al. | Apr 1976 | A |
| 3965256 | Leslie | Jun 1976 | A |
| 3974157 | Shetty et al. | Aug 1976 | A |
| 4013784 | Speiser | Mar 1977 | A |
| 4063064 | Saunders et al. | Dec 1977 | A |
| 4076798 | Casey et al. | Feb 1978 | A |
| 4088864 | Theeuwes et al. | May 1978 | A |
| 4132753 | Blichare et al. | Jan 1979 | A |
| 4259314 | Lowey | Mar 1981 | A |
| 4343789 | Kawata et al. | Aug 1982 | A |
| 4366172 | Lednicer | Dec 1982 | A |
| 4380534 | Fukui et al. | Apr 1983 | A |
| 4389393 | Schor et al. | Jun 1983 | A |
| 4421736 | Walters | Dec 1983 | A |
| 4483847 | Augart | Nov 1984 | A |
| 4533562 | Ikegami et al. | Aug 1985 | A |
| 4613619 | Sleigh et al. | Sep 1986 | A |
| 4708874 | De Haan et al. | Nov 1987 | A |
| 4797410 | El-Fakahany | Jan 1989 | A |
| 4801458 | Hidaka et al. | Jan 1989 | A |
| 4801460 | Goertz et al. | Jan 1989 | A |
| 4828836 | Elger et al. | May 1989 | A |
| 4834984 | Goldie et al. | May 1989 | A |
| 4834985 | Elger et al. | May 1989 | A |
| 4844907 | Elger et al. | Jul 1989 | A |
| 4844909 | Goldie et al. | Jul 1989 | A |
| 4861598 | Oshlack | Aug 1989 | A |
| 4880830 | Rhodes | Nov 1989 | A |
| 4894234 | Sharma et al. | Jan 1990 | A |
| 4917899 | Geoghegan et al. | Apr 1990 | A |
| 4925675 | Giannini et al. | May 1990 | A |
| 4935246 | Ahrens | Jun 1990 | A |
| 4987136 | Kreek et al. | Jan 1991 | A |
| 4990341 | Goldie et al. | Feb 1991 | A |
| 5007790 | Shell | Apr 1991 | A |
| 5023089 | Sakamoto et al. | Jun 1991 | A |
| 5026560 | Makino et al. | Jun 1991 | A |
| 5030400 | Danielsen et al. | Jul 1991 | A |
| 5071646 | Malkowska et al. | Dec 1991 | A |
| 5073379 | Klimesch et al. | Dec 1991 | A |
| 5126145 | Evenstad et al. | Jun 1992 | A |
| 5132142 | Jones et al. | Jul 1992 | A |
| 5133974 | Paradissis et al. | Jul 1992 | A |
| 5162117 | Stupak et al. | Nov 1992 | A |
| 5167964 | Muhammad et al. | Dec 1992 | A |
| 5169645 | Shukla et al. | Dec 1992 | A |
| 5178868 | Malmqvist-Granlund et al. | Jan 1993 | A |
| 5196203 | Boehm | Mar 1993 | A |
| 5202128 | Morella et al. | Apr 1993 | A |
| 5204119 | Shiobara et al. | Apr 1993 | A |
| 5266331 | Oshlack et al. | Nov 1993 | A |
| 5271934 | Goldberg et al. | Dec 1993 | A |
| 5273760 | Oshlack et al. | Dec 1993 | A |
| 5286493 | Oshlack et al. | Feb 1994 | A |
| 5292461 | Juch et al. | Mar 1994 | A |
| 5300300 | Egidio et al. | Apr 1994 | A |
| 5321012 | Mayer et al. | Jun 1994 | A |
| 5330766 | Morella et al. | Jul 1994 | A |
| 5395626 | Kotwal et al. | Mar 1995 | A |
| 5403593 | Royce | Apr 1995 | A |
| 5453283 | Münch et al. | Sep 1995 | A |
| 5456921 | Mateescu et al. | Oct 1995 | A |
| 5468744 | Raffa et al. | Nov 1995 | A |
| 5472710 | Klokkers-Bethke et al. | Dec 1995 | A |
| 5472712 | Oshlack et al. | Dec 1995 | A |
| 5478577 | Sackler et al. | Dec 1995 | A |
| 5521178 | Nickel et al. | May 1996 | A |
| 5549912 | Oshlack et al. | Aug 1996 | A |
| 5580578 | Oshlack et al. | Dec 1996 | A |
| 5591452 | Miller et al. | Jan 1997 | A |
| 5603956 | Mateescu et al. | Feb 1997 | A |
| 5616343 | Cartilier et al. | Apr 1997 | A |
| 5639476 | Oshlack et al. | Jun 1997 | A |
| 5849240 | Miller et al. | Dec 1998 | A |
| 5885615 | Chouinard et al. | Mar 1999 | A |
| 5891471 | Miller et al. | Apr 1999 | A |
| 5958452 | Oshlack et al. | Sep 1999 | A |
| 5958459 | Chasin et al. | Sep 1999 | A |
| 5965161 | Oshlack et al. | Oct 1999 | A |
| 5965163 | Miller et al. | Oct 1999 | A |
| 5968551 | Oshlack et al. | Oct 1999 | A |
| 6068855 | Leslie et al. | May 2000 | A |
| 6103261 | Chasin et al. | Aug 2000 | A |
| 6143322 | Sackler et al. | Nov 2000 | A |
| 6143353 | Oshlack et al. | Nov 2000 | A |
| 6162467 | Miller et al. | Dec 2000 | A |
| 6254887 | Miller et al. | Jul 2001 | B1 |
| 6261599 | Oshlack et al. | Jul 2001 | B1 |
| 6294195 | Oshlack et al. | Sep 2001 | B1 |
| 6306438 | Oshlack et al. | Oct 2001 | B1 |
| 6326027 | Miller et al. | Dec 2001 | B1 |
| 6335033 | Oshlack et al. | Jan 2002 | B1 |
| 6338859 | Leroux et al. | Jan 2002 | B1 |
| 6399096 | Miller et al. | Jun 2002 | B1 |
| 6419957 | Lenaerts et al. | Jul 2002 | B1 |
| 6607748 | Lenaerts et al. | Aug 2003 | B1 |
| 6645527 | Oshlack et al. | Nov 2003 | B1 |
| 6743442 | Oshlack et al. | Jun 2004 | B1 |
| 20030124184 | Mezaache et al. | Jul 2003 | A1 |
| Number | Date | Country |
|---|---|---|
| 2131350 | Mar 1995 | CA |
| 3602370 | Aug 1987 | DE |
| 3623193 | Jan 1988 | DE |
| 4329794 | Mar 1995 | DE |
| 4329794 | Mar 1995 | DE |
| 0032004 | Dec 1980 | EP |
| 0043254 | Jan 1982 | EP |
| 0097523 | Aug 1983 | EP |
| 0043254 | May 1984 | EP |
| 0108218 | May 1984 | EP |
| 0108218 | May 1984 | EP |
| 0147780 | Dec 1984 | EP |
| 0147780 | Jul 1985 | EP |
| 0152379 | Aug 1985 | EP |
| 0214735 | Jul 1986 | EP |
| 0189861 | Aug 1986 | EP |
| 0248548 | May 1987 | EP |
| 0249347 | May 1987 | EP |
| 0251459 | May 1987 | EP |
| 0253104 | Jun 1987 | EP |
| 0254978 | Feb 1988 | EP |
| 0256127 | Feb 1988 | EP |
| 0256127 | Feb 1988 | EP |
| 0267702 | May 1988 | EP |
| 0271193 | Jun 1988 | EP |
| 0271193 | Jun 1988 | EP |
| 0300897 | Jul 1988 | EP |
| 0295212 | Dec 1988 | EP |
| 0327295 | Aug 1989 | EP |
| 0338383 | Oct 1989 | EP |
| 0068450 | Jan 1990 | EP |
| 0351580 | Jan 1990 | EP |
| 0377518 | Jan 1990 | EP |
| 0361680 | Apr 1990 | EP |
| 0361910 | Apr 1990 | EP |
| 0368247 | May 1990 | EP |
| 0377517 | Jul 1990 | EP |
| 0377518 | Jul 1990 | EP |
| 0298355 | Nov 1990 | EP |
| 0415693 | Mar 1991 | EP |
| 0430287 | Jun 1991 | EP |
| 0463833 | Jun 1991 | EP |
| 0241615 | Sep 1991 | EP |
| 0452145 | Oct 1991 | EP |
| 0531611 | Apr 1992 | EP |
| 0535841 | Sep 1992 | EP |
| 0526862 | Feb 1993 | EP |
| 0533297 | Mar 1993 | EP |
| 0534628 | Mar 1993 | EP |
| 0546676 | Jun 1993 | EP |
| 0595311 | May 1994 | EP |
| 0361910 | Jun 1994 | EP |
| 0636370 | Feb 1995 | EP |
| 0642788 | Mar 1995 | EP |
| 0609961 | Aug 1995 | EP |
| 0205282 | Sep 1995 | EP |
| 0624366 | May 1996 | EP |
| 2642420 | Mar 1990 | FR |
| 997399 | Apr 1964 | GB |
| 1405088 | Jun 1971 | GB |
| 1513166 | Jun 1978 | GB |
| 2111386 | Dec 1982 | GB |
| 2117239 | Mar 1983 | GB |
| 2053681 | Apr 1984 | GB |
| 2196848 | May 1988 | GB |
| 2246514 | Feb 1992 | GB |
| 2287880 | Oct 1995 | GB |
| 5492631 | Jul 1979 | JP |
| 4217925 | Aug 1992 | JP |
| 2568202 | Dec 1996 | JP |
| WO 9119484 | Dec 1991 | WO |
| WO 9119485 | Dec 1991 | WO |
| 9201446 | Feb 1992 | WO |
| WO 9201446 | Feb 1992 | WO |
| WO 9202209 | Feb 1992 | WO |
| WO 9205774 | Apr 1992 | WO |
| WO 9206679 | Apr 1992 | WO |
| WO 9300076 | Jan 1993 | WO |
| WO 9304675 | Mar 1993 | WO |
| WO 9307859 | Apr 1993 | WO |
| WO 9307861 | Apr 1993 | WO |
| WO 9317667 | Sep 1993 | WO |
| WO 9318753 | Sep 1993 | WO |
| WO 9324110 | Dec 1993 | WO |
| WO 9403160 | Feb 1994 | WO |
| WO 9403161 | Feb 1994 | WO |
| WO 9405262 | Mar 1994 | WO |
| WO 9422431 | Oct 1994 | WO |
| WO 9423700 | Oct 1994 | WO |
| WO 9514460 | Jun 1995 | WO |
| 03072025 | Sep 2003 | WO |
| 03072089 | Sep 2003 | WO |
| 04000197 | Dec 2003 | WO |
| 04080447 | Sep 2004 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20010036477 A1 | Nov 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 08677798 | Jul 1996 | US |
| Child | 09800204 | US | |
| Parent | 08241129 | May 1994 | US |
| Child | 08677798 | US |
