LUPIN EX. 1010
`Lupin v. iCeutica
`US Patent No. 8,999,387
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`WO 2006/133954 A2
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`For two-letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations ” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
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`WO 2006/133954
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`PCT/EP2006/005799
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`1
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`DICLOFENAC FORMULATIONS AND METHODS OF USE
`
`RELATED APPLICATIONS
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`This application claims priority under 35 U.S.C. § ll9(e) to United States Provisional
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`Patent Application Nos. 60/692,024 (filed June 17, 2005), and 60/691,757 (filed June 17,
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`2005).
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`FIELD OF THE INVENTION
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`This invention concerns methods and formulations for treating migraine and other
`
`acute pain episodes using diclofenac, and formulations of diclofenac that provide both rapid
`and sustained relief from acute pain.
`The invention further concerns methods and
`
`formulations for treating symptoms that often accompany migraine and acute pain such as
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`rebound headache, photophobia, phonophobia, nausea and vomiting.
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`BACKGROUND OF THE INVENTION
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`Diclofenac is a non-steroidal anti-inflammatory drug (“NSAID”) known chemically
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`as [(2,6-dichloro- anilino)-2-phenyl]-2-acetic acid. The drug was developed in the 1960s by
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`scientists at'Ciba—Geigy and is sold around the world by‘ Novartis under various trade names,
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`including Cataflam® and Voltaren
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`® in the United States.
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`A wet granulated formulation of
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`diclofenac potassium was recently developed to provide an increased rate of absorption, and
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`its pharmacokinetic properties tested against commercially available diclofenac potassium
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`tablets.
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`(Reiner et al., Increased absorption rate of diclofenac from fast acting formulations
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`containing its potassium salt. Arzniem.-Forsch./ Drug Res. 2001; 51:885-890.) According to
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`the authors, the granular fonnulation showed a higher Cmax than the diclofenac potassium
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`tablets, a shorter tmax (i.e. time to Cmax) and a similar AUC when compared to the tablet form.
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`Owing to its excellent analgesic properties, diclofenac is widely used for treating
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`various types of pain,
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`including both chronic and acute painful episodes. The drug is
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`administered for the treatment of musculoskeletal and joint disorders such as rheumatoid
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`arthritis, osteoarthritis, and ankylosing spondylitis; periarticular disorders such as bursitis and
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`tendonitis; soft tissue disorders such as sprains and strains, and other painful conditions such
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`as
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`renal colic, acute gout, dysmenorrhoea, and following some surgical procedures.
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`(Martindale (2000) Diclofenac.
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`In: Reynolds, The Extra Pharmacopoeia. London: The
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`Pharmaceutical Press; p. 31-33.) Diclofenac has also been studied for the treatment of
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`headache pain from migraine attacks, using various doses and dosage forms, including 75
`
`mg. intramuscular injections (Del Bene et al., Intramuscular treatment of migraine attacks
`
`using diclofenac sodium: a cross-over trial.
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`J. Int. Med. Res. 1987; 1544-8), 100 mg.
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`suppositories (Del Bene et al., Migraine attack treatment with diclofenac sodium. Cephalalgia
`1985; 5:144-5), and 50 mg. enteric coated tablets.
`(Massiou et al., Effectiveness of oral
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`diclofenac in the acute treatment of common migraine attacks: a double blind study versus
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`placebo. Cephalalgia 1991; 1:59-63.)
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`Migraine attacks manifest a diverse array of symptoms that must be resolved in order
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`for a treatment to be deemed truly effective against migraine (instead of just treating the
`
`symptoms).
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`In particular, the treatment must be effective against the pain, photophobia,
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`phonophobia and nausea that are caused by migraine, and it must be effective within the first
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`two hours of treatment, in order to be considered a true treatment for migraine. None of the
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`studies reported to date suggests that a 50 mg. diclofenac product could treat all of these
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`symptoms within two hours of treatment.
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`In 1993, investigators studied 100 mg. and 50 mg. diclofenac tablets, in comparison to
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`placebo, and determined that both strengths were effective against migraine pain within two
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`hours of treatment, but that only the 100 mg. strength was effective against phonophobia and
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`photophobia within two hours. (Dahlof et al., Diclofenac—K (50 and 100 mg.) and placebo in
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`the acute treatment of migraine. Cephalalgia 1993; 132117-123).
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`In 1999, a separate group of
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`investigators tested 50 mg. and 100 mg. sugar coated tablets of diclofenac potassium to treat
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`migraine, and once again confirmed the ability of both doses to relieve migraine pain within
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`two hours of treatment.
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`(The Diclofenac—K/Sumatriptan Migraine Study Group, Acute
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`treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug,
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`diclofenac potassium,
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`in comparison to oral sumatriptan and placebo. Cephalalgia 1999;
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`l9:232-40.) The investigators concluded that neither dose was effective against photophobia
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`two hours after treatment, that both doses were effective against photophobia eight hours
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`after treatment, that only the 100 mg dose was effective against phonophobia two hours after
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`treatment, and that the 50 mg dose was effective against photophobia eight hours after
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`treatment.
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`The 1999 investigators also studied the effectiveness of 100 mg and 50 mg.
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`diclofenac-K immediate release tablets at preventing recurrence of headaches within 48 hours
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`of treatment. The investigators concluded that patients treated with the 50 mg and the 100
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`mg diclofenac-K tablets actually had a higher incidence of headache recurrence than patients
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`treated with placebo (i.e. that the diclofenac—K performed worse than placebo), although the
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`statistical significance of these findings is not reported.
`This latter finding is consistent with other recent literature which recommends the use
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`of a “long acting NSAID” to reduce the frequency of rebound headaches. For example,
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`Plachetka recommends in U.S. Patent No. 6,586,458 that triptan therapy be augmented with a
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`“long acting NSAID” to provide “a substantial reduction in the frequency [of] relapse of
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`headaches.” Diclofenac potassium is not considered a long acting NSAID because it displays
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`an average Cmax within only about one hour and a terminal half life of only about 1.9 hours
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`when administered in commercially available sugar coated tablets.
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`Diclofenac is generally taken orally in the form of normal tablets or tablets covered
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`with coatings resistant to gastric juices, or rectally, or by injection, or topically. Recently,
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`however, in W0 97/44023, Reiner et al. proposed to administer diclofenac in a number of
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`less conventional dosage forms — including as a powder sachet for oral administration after
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`dissolving in water -- for quicker onset of analgesic relief. One of the primary obstacles in
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`the manufacture of powder sachets is the distribution of the drug in the powder, and the
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`uniformity of content in the finished product. These hurdles are magnified in the production
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`of diclofenac sachets due to the poor aftertaste of diclofenac, and the need to incorporate
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`additional ingredients to compensate for this poor taste.
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`To ensure an adequately homogenous distribution of drug product in the bulk powder,
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`Reiner et al. disclose a wet granulation process for manufacturing the powder sachets.
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`In the
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`first step of the process, a wet granulate is prepared from diclofenac potassium, potassium
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`bicarbonate, saccharin, aspartame and mannitol, using 95% ethanol as the wetting agent. The
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`granulate is then mixed with over one gram of sugar (saccharose) and various flavoring
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`agents to improve the taste of the composition.
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`The method described by Reiner et al. produces an excellent pharmaceutical dosage
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`form but suffers from a number of disadvantages including the size of the sachet (2g) which
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`makes the sachet more difficult to dissolve, and the presence of sugar in the formulation,
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`which should be avoided in the diabetic population.
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`In addition, the process requires precise
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`controls on the granulometric process to assure uniform distribution of drug in the granulate
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`and consistent amounts of drug in the finished product. What is needed is an alternative
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`method for producing sugar-free powder diclofenac sachets and other fast acting dosage
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`forms of diclofenac.
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`SUMMARY OF INVENTION
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`The inventors have unexpectedly discovered that rapidly bioavailable formulations of
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`diclofenac are effective in the treatment of migraine and other acute pain episodes, and that in
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`spite of their quick onset of action, they provide sustained relief against acute pain for up to
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`twenty—four hours. Contrary to the prior art, which suggests that a long acting NSAID should
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`be used to prevent rebound headache, and that a rapidly bioavailable formulation of
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`diclofenac would be ineffective against rebound headache, the inventors have discovered that
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`a rapidly bioavailable formulation of diclofenac, as measured by tmax and Cmax, prevents
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`recurrence of headaches for at
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`least
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`twenty four hours after treatment
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`in a significant
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`population of migraine sufferers.
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`In addition, the consistency of bioavailability seems to
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`improve as the bioavailability of the molecules becomes more rapid, which further
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`contributes to the clinical efficacy observed for these formulations.
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`The inventors have also surprisingly discovered that
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`these rapidly bioavailable
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`.formulations relieve symptoms often associated with migraine and other acute pain, including
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`photophobia and phonophobia, better than conventional immediate release tablets. These
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`results are surprisingly seen even though the diclofenac in these formulations is more rapidly
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`eliminated from the bloodstream than conventional immediate release tablets of diclofenac,
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`and even though the total amount of diclofenac absorbed in the blood stream (measured as
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`the area under the curve (i.e. AUCo_¢.,))
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`is comparable for the two formulations. The
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`formulations are thus able to meet all of the primary clinical endpoints for evaluating
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`migraine treatments, and for completely treating migraine.
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`Therefore, in one embodiment the invention preferably provides a method of treating
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`migraine comprising: (a) providing a liquid formulation comprising 50 mg. of diclofenac or a
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`pharmaceutically acceptable salt thereof, wherein said formulation: (i) is provided as a unit
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`dose powder
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`formulation and dissolved or
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`suspended in water
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`immediately before
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`administration, or as a unit dose liquid formulation that is ingested with or without further
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`mixing; (ii) achieves tmax in from about 10 to about 20 minutes; and (iii) optionally but
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`preferably achieves a Cmax of from about 1500 to about 2500 ng/ml; and (b) orally
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`administering said formulation to a patient suffering from migraine, wherein migraine is
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`defined as a disease manifested in a population of patients by periodic attacks of headache
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`pain, nausea, photophobia and phonophobia.
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`In one particular embodiment the method is
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`used to treat migraine that is accompanied by photophobia and/or phonophobia. In another
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`particular embodiment,
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`the method is used to treat migraine patients who suffer from
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`recurrent headache, and are diagnosed as requiring relief from recurrent headache within
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`twenty—four hours of the initial treatment.
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`In other embodiments the method is used to treat any episode of acute pain in which
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`the pain would otherwise persist for at least about eight hours, and pain relief is required for
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`this time period. Thus,
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`in still another embodiment the invention preferably provides a
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`method of treating acute pain in a human patient requiring pain relief for at least eight hours,
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`comprising: (a) providing an oral formulation comprising about 50 mg. of diclofenac or a
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`pharmaceutically acceptable salt thereof, wherein said formulation(ii) achieves tmax in from
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`about 10 to about 35, 30, or 25 minutes; and (iii) optionally but preferably achieves a Cmax of
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`from about 1400 or 1500 to about 2500 ng/ml; and (b) orally administering said formulation
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`to a patient suffering from acute pain, preferably no more than 3 total times in a 24 hour
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`period.
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`In still another embodiment
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`the invention provides an alternative method for
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`preparing powder diclofenac sachets that is based predominantly on the large proportion of
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`mannitol in the formulation, which preferably includes a precise control of particle size of
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`diluents in the finished product. The large proportion of mannitol imparts surprisingly rapid
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`bioavailability to the formulation, while the control of particle size assures uniform
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`distribution of diclofenac in the material used to fill the sachets and consistent amounts of
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`drug in each sachet without the use of sugar or large amounts of diluent as taught in the prior
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`art. The method and powders produced by the method are characterized by, among other
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`variables, (1) the ratio of the diluent to the diclofenac in the powder, (2) a combination of
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`particle sizes of the diluent in the final composition, and (3) the sequence of mixing the
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`diclofenac and the varying particle sizes of diluent.
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`The invention further provides methods for manufacturing highly concentrated liquid
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`formulations of diclofenac that can be drawn as drops from a bottle and administered after
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`mixing the diclofenac with a suitable carrier such as water. In one aspect of this embodiment
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`the invention provides a method of making a liquid solution of diclofenac, wherein the
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`diclofenac is present in the liquid at a concentration of from about 10 to about 100 mg./ml.,
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`comprising (a) dissolving diclofenac in ethyl alcohol to form a solution, (b) mixing said
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`solution with glycerol to form a second solution, and (c) mixing said second solution with
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`water.
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`Additional advantages of the invention will be set forth in part in the description
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`which follows, and in part will be obvious from the description, or may be learned by practice
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`of the invention. The advantages of the invention will be realized and attained by means of
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`the elements and combinations particularly pointed out in the appended claims. It is to be
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`understood that both the foregoing general description and the following detailed description
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`are exemplary and explanatory only and are not restrictive of the invention, as claimed.
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`DETAILED DESCRIPTION OF THE DRAWING
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`The accompanying drawing,.which is incorporated in and constitutes a part of this
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`specification,
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`illustrates several embodiments of the invention and together with the
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`description, serves to explain the principles of the invention.
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`Figure 1
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`is a flow diagram illustrating a non—granulate method and sequence of
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`mixing employed in making 900 mg. powder sachets of the instant invention that contain 50
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`mg. of diclofenac potassium.
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`DETAILED DESCRIPTION OF THE INVENTION
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`The present invention may be understood more readily by reference to the following
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`detailed description of preferred embodiments of the invention and the Examples included
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`therein.
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`Methods of Treating Migyaine and Acute Pain
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`As discussed above,
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`the‘ invention provides novel formulations of diclofenac —
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`especially diclofenac potassium —-
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`that have proven to be remarkably effective against
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`migraine headache and other forms of acute pain. The formulations may contain various
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`quantities of diclofenac, in various oral dosage forms, ranging from about 12.5 mg. to about
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`100 mg. of diclofenac or a pharmaceutically acceptable salt thereof. Thus, for example, the
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`formulation can contain about 12.5, 25, 37.5, 50, 75 or 100 mg of diclofenac or a
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`pharmaceutically acceptable salt thereof, in a tablet, a capsule, a powder for oral solution, an
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`oral solution or suspension, on orally dissolving tablet, a mucoadhesive film, or any other
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`orally ingestable dosage form.
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`In a particularly preferred embodiment, however,
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`the
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`formulations of the present invention are present in a liquid form when ingested, and they
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`contain about 50 mg. of diclofenac or a pharmaceutically acceptable salt thereof.
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`In another
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`preferred embodiment, the formulations are used to treat migraine headache.
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`Therefore, in one embodiment the invention provides a method of treating migraine
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`comprising:
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`(a) providing a liquid formulation comprising 50 mg. of diclofenac or a
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`pharmaceutically acceptable salt thereof, wherein said formulation: (i) is provided as a unit
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`close powder
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`formulation and dissolved or suspended in water
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`immediately before
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`administration, or as a unit dose liquid formulation that is ingested with or without further
`
`mixing; (ii) achieves tmax in from about 10 to about 20 minutes; (iii) optionally but preferably
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`achieves a Cmax of from about 1500 to about 2500 ng/ml; and (b) orally administering said
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`formulation to a patient suffering from migraine, wherein migraine is defined as a disease
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`manifested in a population of patients by periodic attacks of headache pain, nausea,
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`photophobia and phonophobia.
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`In one particular embodiment, the methods of this invention are used to treat some of
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`the most difficult to treat migraine patients — i.e. those whose headache pain is likely to recur
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`within twenty-four hours of initial treatment, or those who also suffer from photophobia or
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`phonophobia. Therefore, in another embodiment the invention provides a method of treating
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`migraine in a human patient suffering from migraine comprising: (a) providing a liquid
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`formulation comprising about 50 mg. of diclofenac or a pharmaceutically acceptable salt
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`thereof, wherein said formulation: (i) is provided as a powder formulation and dissolved or
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`_ suspended in water immediately before administration, or as a liquid formulation that is
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`ingested with or without further mixing; (ii) achieves tmax in from about 10 to about 2
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`minutes; (iii) optionally but preferably achieves a Cmax of from about 1500 to about 2500
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`ng/ml; and (b) diagnosing a patient suffering from migraine as requiring sustained migraine
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`relief for at least 24 hours (such as a patient who is susceptible to rebound or recurrent
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`headaches); and (c) orally administering said formulation to said patient.
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`Patients who are particularly well—suited for treatment by the methods of this
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`invention are those patients who have previously been treated for migraine pain using an
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`acute pain medication, but who continued to suffer from symptoms such as phonophobia,
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`photophobia, nausea and vomiting, especially those individuals who required additional
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`medication for these symptoms. Thus, for example,
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`in one embodiment the patient has
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`previously been diagnosed as requiring relief from photophobia, phonophobia, nausea or
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`vomiting in conjunction with treatment for migraine pain.
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`In another embodiment the
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`method is performed without administering other medications for the relief of photophobia,
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`phonophobia, nausea or vomiting.
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`In still another embodiment the method is performed
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`without administering other medications for the relief of migraine pain.
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`Therefore, in still another embodiment the invention provides a method of treating
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`migraine associated with phonophobia or photophobia in a human patient comprising: (a)
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`providing a liquid formulation comprising 50 mg. of diclofenac or a pharmaceutically
`
`acceptable salt thereof, wherein said formulation: (i) is provided as a powder formulation and
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`dissolved or suspended in water immediately before administration, or as a liquid formulation
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`that is ingested with or without further mixing; (ii) achieves tmax in from about 10 to about 20
`
`minutes; (iii) optionally but preferably achieves a Cmax of from about 1500 to about 2500
`
`ng/ml; and (b) orally administering said formulation to a patient suffering from migraine
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`associated with photophobia or phonophobia.
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`As discussed above, this invention also concerns methods for treating acute pain using
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`diclofenac, and formulations of diclofenac that provide immediate and sustained relief from
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`any type of acute pain.
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`In addition to migraine headache pain, the pain may derive from a
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`variety of sources, including musculoskeletal and joint disorders such as rheumatoid arthritis,
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`osteoarthritis, and ankylosing spondylitis, periarticular disorders such as bursitis and
`
`.tendonitis, soft tissue disorders such as sprains and strains, and other painful conditions such
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`as renal colic, acute gout, dysmenorrhoea, and following some surgical procedures.
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`In one
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`preferred embodiment the acute pain is post-operative pain, such as post-operative dental
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`pain.
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`The formulations are particulany well suited for providing relief from sustained acute
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`pain, defined herein as acute pain that would otherwise persist for about 4, 6 or 8 hours
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`without the treatment contemplated by the current invention.
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`In one preferred embodiment
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`the patient treated by the method has been previously diagnosed as requiring relief from
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`sustained acute pain. A patient requiring sustained relief from acute pain is a patient who has
`either been previously diagnosed as requiringirescue medication within about 4, 6 or 8 hours
`
`of treatment for said acute pain, or a patient whose acute pain is expected to persist for 4, 6 or
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`8 or more hours in the absence of treatment.
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`In another embodiment, therefore, the invention provides a method of treating acute
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`pain in a human patient requiring pain relief for at least eight hours, comprising: (a) providing
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`an oral formulation comprising about 50 mg. of diclofenac or a pharmaceutically acceptable
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`salt thereof, wherein said fonnulation: (i) achieves a Cmax of from about 1400, 1450 or 1500
`
`to about 2500 ng/ml; and (ii) achieves tmax in from about 10 to about 35, 30 or 25 minutes;
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`and (b) orally administering said formulation to a patient suffering from acute pain,
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`preferably no more than 3 total times in a 24 hour period.
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`The sustained relief provided by the compositions of the present invention provides
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`numerous advantages in the treatment of acute pain, and leads to decreased requirements for
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`pain medication by many patients. Thus,
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`in one embodiment the method is performed
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`without administering other immediate pain relief or rescue medications within the first 4, 6
`
`or 8 hours of administering the diclofenac formulation.
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`In one embodiment, the formulation
`
`is administered no more than 3 total times in a 24 hour period.
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`In another embodiment, the
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`formulation is administered as needed for pain every 2, 4, 6 or 8 hours (or every 4-6, 4-8, or
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`6-8 hours), as needed for pain, preferably not to exceed three times per day.
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`In yet another
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`embodiment, the formulation is administered once every eight hours.
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`As discussed above,
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`the formulations of the present
`
`invention are preferably
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`administered as a liquid for oral ingestion, and can be provided in any form suitable for such
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`administration.
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`In a particularly preferred embodiment, the formulation is provided in a
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`single unit dose as a powder sachet, which is mixed with water before administration.
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`In
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`other embodiments the formulation is already dissolved in a liquid, as in the drop formulation
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`of the present invention and the unit dose vials discussed elsewhere herein.
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`It will be
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`understood, however, that the relief from migraine and acute pain occasioned by the methods
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`of the present
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`invention can be achieved with any oral
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`formulation that achieves the
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`pharmacokinetics described herein, and that the invention extends to any such dosage form.
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`Statistically Significant Relief
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`In some embodiments of the present invention, the medication is administered to a
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`plurality of patients suffering from migraine, and statistically significant relief is observed
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`based on one or more primary or secondary clinical endpoints, in comparison to placebo or
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`50 mg. immediate release diclofenac potassium tablets (i.e. Cataflam), including:
`
`0
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`two hour pain relief (i.e. a decrease in pain intensity from moderate/severe to
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`mild/none)
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`pain free at two hours
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`sustained pain relief for 6, 8 or 24 hours
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`relief from phonophobia at two hours
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`relief from photophobia at two hours
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`relief from nausea and vomiting at two hours
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`0
`
`0
`
`0
`
`0
`
`0
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`As noted above, the ability to attain statistically significant relief by the methods of the
`
`present invention is greatly influenced by the coefficients of variation in Cmax and tmax
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`observed for this invention, which seem to decrease as the diclofenac in these formulations
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`becomes more bioavailable.
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`Of course, every patient treated by the methods of the present invention will not
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`require relief from every clinical endpoint, or obtain relief from every clinical endpoint.
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`In
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`addition, the plurality of patients that any individual physician or physician’s practice group
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`treats may not rise to the level of “statistical significance,” as that term is typically used in the
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`pharmaceutical industry (i.e. p < 0.05).
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`In the context of this invention, the term “statistically
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`significant” is not based solely upon the plurality of patients treated by the defined method,
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`but takes into account well designed comparative clinical trials versus placebo that have
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`previously been conducted to confirm the statistically significant relief, in addition to the
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`clinical
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`results obtained by practice of the present
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`invention by individual patients,
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`practitioners, or physician practice groups.
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`Pharrnacokinetics
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`In one embodiment the composition is characterized by its pharmacokinetics, such as
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`Cmax (i.e. average concentration of active chemical in the bloodstream after oral ingestion,
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`preferably in the fasted state), and its tmax (i.e. average time to reach said Cmax, in a fasted
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`state).
`
`In a particularly preferred embodiment,
`
`the mean Cmax for a 50 mg. diclofenac
`
`composition ranges from about 1300, 1400, 1500, 1600 or 1700 to about 2600, 2500, 2300,
`
`2100, 2000 or 1900 ng/ml. A suitable range can be derived from any of these upper and
`
`lower bounds, but in one embodiment the formulation preferably attains a Cmax of from about
`
`1300, 1400 or 1500 to about 2500 ng/ml; or from about 1500, 1600, or 1700 to about 2100
`
`ng/ml, for a 50 mg. diclofenac formulation.
`
`It will be understood, of course that any of these
`
`Cmax values can be normalized based on the dose administered. Thus, for example, a 1500
`
`ng/ml Cmax observed for a 50 mg. dose, could be normalized to 30 ng/ml-g and applied to
`
`other close amounts.
`
`In a particularly preferred embodiment the formulations yield only one
`
`peak concentration when blood concentrations are plotted against time.
`
`The median tmax (i.e. time to reach Cmax) of the formulations is preferably from about 5
`
`or 10 to about 40, 35, 30, 25 or 20 minutes. Once again, a suitable range can be derived from
`
`any of these upper and lower bounds, but in one particular embodiment the tmax of the
`
`formulation is most preferably from about 10 to about 35 minutes, from about 10 to about 30
`
`minutes, from about 10 to about 25 minutes, or from about 10 to about 20 minutes. The
`
`inter-subject coefficient of variability for said Cmax preferably is less than about 70, 65, 60,
`
`55, 50, 40 or 35%, and the inter-subject coefficient of variability for said tmax is preferably
`
`less than about 70, 60, 50, 40 or 35%.
`
`Of course, it will be understood that bioavailability can differ from different study
`
`sites. When a single formulation gives results that vary significantly among different clinical
`
`sites
`
`and investigators,
`
`the results
`
`can be proportionately normalized against
`
`the
`
`bioavailability of Cataflam tablets, based upon the results reported in the examples hereto.
`
`Thus, for example, if the Cm, that a laboratory observes for Cataflam is only 750 ng/ml, all
`
`of the Cmax results reported from the laboratory could be adjusted by a factor of
`
`(1'037.124)/(750).
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`WO 2006/133954
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`PCT/EP2006/005799
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`12
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`Methods of Formulation
`
`As noted previously, the invention also concerns methods of making a particulate
`
`flowable diclofenac composition that can be defined by a number of characteristics, including
`
`the presence of a fine powdered diluent, the combination of fine and coarse diluent, the total
`
`amount of diluent,
`
`the size distribution of diclofenac particles, or the use of a non-
`
`hygroscopic diluent. These various features and aspects of the present invention are set forth
`
`in greater detail below.
`
`Diclofenac
`
`The diclofenac used in the present invention can be defined by various parameters. In
`
`one embodiment, the raw material will be a powder that exhibits no more than 0.5 wt.% loss
`
`on drying.
`
`In another embodiment not less than 90% of the diclofenac particles are less than
`
`.500 micrometers in diameter, not less than 40% and not more than 70% of the particles are
`
`less than 200 micrometers in diameter, not less than 35% and not more than 65% of the
`
`particles are less than 150 micrometers in diameter, and not less than 30% of the particles are
`
`less than 100 micrometers in diameter.
`
`(Analyses performed using sieves according to the
`
`Sieve Test 2.9.12 Eur.Ph.
`
`-— Alpine Air Jet Sieve.) The average particle size for the
`
`diclofenac powder is preferably about 150, 160, 170, 180, 190, 200, 210, 220, 230, or 240
`
`micrometers, and can range between any two of the foregoing variables (i.e. from about 150
`
`to about 230 micrometers, or from about 170 to about 220 micrometers).
`
`The diclofenac can be present
`
`in acid or salt form although, owing to its poor
`
`solubility in water, diclofenac is normally used in salt form. The salts of diclofenac
`
`customarily used are those of sodium, potassium or other alkali and alkaline earth metals,
`
`together with salts of organic nature, such as the salts of basic amino acids, such as lysine,
`
`arginine and omithine, or other pharmacologically acceptable organic bases which have the
`
`ability to render the resulting salt soluble in water. Diclofenac potassium is preferably used
`
`in this invention due to its fast onset of action.
`
`In a preferred embodiment, 50 mg. of diclofenac or its salt is used in the final dosage
`
`form, although other amounts could be used including 12.5, 25, 37.5, 50, 75 or 100 mg of
`
`diclofenac, or a range having as endpoints any of the foregoing amounts. The amount of
`
`diclofenac preferably does not vary by more than about 95-105% from dose to dose.
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`Page 14
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`WO 2006/133954
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`PCT/EP2006/005799
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`13
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`Buffering Agents
`
`Buffering agents are not critical to the invention, but are preferably used to provide a
`
`rapid rate of onset for the final pharmaceutical product.
`
`In a preferred embodiment for
`
`powder sachets, the buffering agent controls the pH of the formulation when dissolved in
`
`water, and preferably yields a pH greater than about 6.8, 7.0, 7.2, or 7.4, and less than about
`
`7.8, 7.7 or 7.6, when mixed with 50 ml or 100 or 200 ml. of water at 25 degrees Celsius.
`
`Particularly preferred buffering agents are alkali metal carbonates and bicarbonates
`and these agents are preferably employed in a weight ratio relative to the diclofenac of
`
`greater than about 1:5, 2:5, 2:1, 3:1 or 5:1. If desired, an upper limit on the buffer:diclofenac
`
`ratio can be placed at about 20:1, 10:1, 5:1, 1:1, 4:5 or 3:5. Ranges can be selected from any
`
`two of the foregoing values that are mathematically possible.
`
`In a preferred embodiment, the
`
`buffer:diclofenac weight ratio ranges from about 1:5 to about 4:5. Particularly preferred
`
`alkali metal bicarbonates are sodium bicarbonate and potassium bicarbonate.
`
`Final Powdered Sachet Product
`
`The powder sachets used in the methods of this invention can be produced by various
`
`methods including dry granulation, wet granulation and dry admixing processes. A suitable
`
`product produced by wet granulation is described, for example, by Reiner et al.
`
`in WO
`
`97/44023.
`
`In one clinical trial, a representative 50 mg. diclofenac formulation obtained by the
`
`method disclosed in examples 3 and 4 was shown to exhibit the following pharmacokinetic
`
`properties:
`
`Cmax mean value
`
`1620 ng/ml (CV= 53.8%)
`
`tmax mean value
`
`13.98 min (CV=32.2%)
`
`AUC 0—t mean value
`
`1010 (CV=42.4%)
`
`In contrast, a 50 mg. formulation prepared by the wet granulation process disclosed in
`
`WO 97/44023 has been s