ZA200602747B - Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation - Google Patents
Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation Download PDFInfo
- Publication number
- ZA200602747B ZA200602747B ZA200602747A ZA200602747A ZA200602747B ZA 200602747 B ZA200602747 B ZA 200602747B ZA 200602747 A ZA200602747 A ZA 200602747A ZA 200602747 A ZA200602747 A ZA 200602747A ZA 200602747 B ZA200602747 B ZA 200602747B
- Authority
- ZA
- South Africa
- Prior art keywords
- clomipramine
- antidepressants
- administration
- ejaculation
- onset
- Prior art date
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- 230000002685 pulmonary effect Effects 0.000 title description 13
- 206010036596 premature ejaculation Diseases 0.000 title description 12
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 239000000935 antidepressant agent Substances 0.000 description 31
- 229940005513 antidepressants Drugs 0.000 description 30
- 230000000694 effects Effects 0.000 description 27
- -1 spontaneous Orgasm Chemical compound 0.000 description 26
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- 239000000203 mixture Substances 0.000 description 21
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- 238000000034 method Methods 0.000 description 8
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- 239000003795 chemical substances by application Substances 0.000 description 7
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- Medicinal Preparation (AREA)
Description
» +
PHARMACEUTICAL COMPOSITIONS FOR TREATING
PREMATURE EJACULATION BY PULMONARY INHALATION
The present inventon relates to improved formulations for the treatment of ) 5 premature ejaculation and, in particular, relates to the administration of anudepressants by pulmonary inhalation for treating premature ejaculation. Various types of known antideprcssanis may be us «d, wdjuding wicyclic antidepressants, such as clomipramine. 70. Premature ejacvlavuon (PE) is the persisterat or recurrent ejaculation with minimal sumulation before, on or shortly after pen etration and before the patient (or partner) wishes it. An occasional instance of PE might not be cause for concern, but if the problem occurs more frequently, a dysfunctional pattern usually exists for which treatment may be appropriate. : -
Male sexual stimulation can be classified a ccording to functional activities during the sexual cycle. The normal male sexual response cycle is divided into five interrelated events that occur in a defined sequence: libido, erection, ejaculation, orgasm and detumescence.
Ejaculation 1s controlled by sympathetic itinervation of the genitals and occurs as a result of a spinal cord reflex, although the re is also considerable voluntary inhibitory control. Ejaculation involves two process es. Emission is associated with the secretion of seminal fluid into the posterior urethra via contractions of the ampulla of the vas deferens, seminal vesicles and Prostate smooth muscle. This is followed by the second phase of expulsion of the seminal fluid through the penis to the outside. An inhibitory effect on ejaculation is thought to be mediated via . serotonergic neurotransmission in the forebrain.
In normal development, men are able to control their ejaculation by the age of 17 or so.
A spectrum of ejaculatory disorders exists, ranging from premature ejaculation through to absence of ejaculation. Premature ejaculation 1s described as the most common male sexual dysfunction with an estimated prevalence of around 30%. .
This estimate varies between 1% and 75% depending on the population and the criteria used to define the condition - ’
A descripuve definition that has been used defines prematuie €jaculaton as "persistent or recurrent ejaculation with minimum sexual stimulation that occurs before, upon or shortly after penetration and before the person wishes it and 1n the absence of substance abuse”. The condition can cause great distress and can place strain on relationships. Therefore, an effective and reliable treatment of PE is highly desirable.
A quantitative definition, the Intra vaginal Ejaculatory Latency Time (IELT), has ;5 also been used as an endpoint to enable the assessment of interventions designed to improve ejaculatory delay. A pers on is considered to have premature ejaculation if the IELT is <60 seconds.
Premature ejaculation can be phy siological in nature (neurological abnormality, acute physical illness, physical inj -ury or pharmacological side effect) or psychological (distress, anxiety, deficit in psychosexual skill). Primary premature ejaculation describes the condition in someone who has had symptoms from the onset of sexual experience, wher eas secondary PE is a sequelae to another condition, for example erectile dysfunction.
PE may be related to a number of different factors including a hypersensitive pervous system, penile sensitivity, somatic vulnerability, lack of inhibitory effect of the serotonergic system and superior reproductive strategy.
Itis believed that ejaculation delay is related to SHT¢ activation, with faster ejaculation associated with 5HT,, activation. It is hypothesised that low SHT neurotransmission or hypofunc tion of the SHT,. receptor or hyperfunction of 5HT,, leads to PE.
1 ih
Treatment of premature ejaculation can be divided into either psychological and ' behavioural counselling or drug therapy. The former can take a number of forms but all are centred on the basic procedure of the stop-start technique. This involves ) 5 the man or his partner stopping stimulation and squeezing the penis, proximal to the frenulum, at the moment immediately before cjaculation. Used in a graduated fashion starting with masturbation and ending with active intercourse this technique has high 1niual success (60-90%) although this may decline over the 3 years after therapy to 25%. 70
There are 2a number of different drug therapy approaches to premature ejaculation.
Much of the early work was done using the tricyclic antidepressants, such as clomipramine, which acts centrally via the 5SHT2 1eceptor to inhibit serotonin reuptake, thereby promoting serotonin activity and effecting a delay in ejaculation.
Daily oral doses of 25-50mg of clomipramine were found to be effective in delaying: rapid ejaculation in Althof, et al. (J Clin Psy chiatry (September 1995) 56:9, p.402- 407). It was concluded from the Tesults of the study that clomipramine is effective in significantly lengthening ejaculatory lateracies and increasing sexual and relationship satisfaction. It was also consid ered to be a cost-effective chronic therapy for selected patents.
There are side effects associated with the use of clomipramine in treating PE, such as Spontaneous orgasm, anorgasmia, and ejaculatory pain. Additionally, there are a range of frequently reported side effects (> 10%) for the oral formulation used for antidepressive indications, including dry mouth, sweating, constipation, blurred vision, nausea, drowsiness, headache and dizziness.
Work has also been carried out with selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft (trade mark)), flu oxetine (Prozac (trade mark)) and paroxetine (Paxil (trade mark)). All of these active agents have been found to be effective in producing a delay in ejaculation following oral administration, although there is generally a significant delay between administration (by ingestion) and the so BN
C@e -4- onset of the therapeutc effect. At present, none of these SSRIs are approved for use in treating PE.
Some early work has been done with alpha-adrenergic receptor blockers, based on the bypothesis that the sympathetic nervous system 1s responsible for the control of ‘ the peristaloc movement of seminal fluid. However, no definitive dosing regimen has been established in larger trials.
Abdel-Hamad, et al. (Int J Impot Rees (2001) Feb; 13(1):41-5) conducted a 70 randomised, double blind, crossov er, comparative study in 31 male patients with primary PE. The study evaluated five different therapies (clomipramine, sertraline, paroxetine, sildenafil and the "squ eeze technique") during a 4-week treatment period with a 2-week washout period. Th e drugs were administered orally some 3 to 5 hours before planned intercourse and not more than twice a week. It was /5 concluded that orally administered clomipramine, sertraline and paroxetine demonstrated comparable efficacy, with sildenafil demonstrating optimal ‘efficacy. 1t was also found that the "on dexnand" use of the drugs was associated with mild and low incidence of side effects when compared with the continuous administration proposed by earlier studies, such as Althof, et al,, discussed above. ‘20
A number of new products are also currently under development, including dapoxetine, a SHT modulator-reuptake inhibitor, SHT3 receptor antagonists and 5HT4 antagonist, and novel fluoxetine formulations.
Limited data are available for the use of topical anaesthetic creams applied to the glans penis and penile shaft in a ssociation with the use of a condom. This treatment has not been formally tested. It seems that analgesia is maximal 2 -3 hours after application and lasts for 1-2 hours depending on method of application.
The vast majority of the drug treatments for PE discussed in the prior art involve Rk oral administration of the active agent. Whilst this is convenient, as oral dosage forms of the antidepressants tend to be readily available, this route of py » ] L” . . 2 4 06/0
WO 2003_/0253550 — 20 PCT/GB2004/003935 -5. administration provides a relatively slow onset of the therapeutic effect, even when the oral dosage forms are formulated for rapid release. of the active agent.
All the tresatments discussed briefly above rely on a hi_gh degree of predictability and ‘ 5 planning -of sexual activity because of the delay between dosing and attainment of effect. It is therefore an aim of the present invention to provide a treatment for
PTeimatures ¢jacuiation which has a rapid onset of the esired therapeutic effect with minimum but adequate duration, thereby allowing important spontaneity of sexual activity arad creating a much more patient-friendly trezmtment than currently exists. 70 Preferably, the onset will be almost instantaneous foll owing administration.
In additio-m, the present invention also seeks to avoid the side effects frequently associated with some of the known treatments discussed above. It is envisaged that this might= be achieved by more efficient administration, so that smaller doses of the therapeutli¢ agent may be administered to achieve the same therapeutic effect. It has also been noted that the side effects associated with tlhe administration of : clomipramine, such as spontaneous Orgasm, anorgasromia, and ejaculatory pain may be due to the relatively unpredictable nature of oral route metabolism and so it may be possibl € to avoid them by using a more predictable. mode of administration. .
Side effecats should also be reduced if the therapeutic agent can be administered on an "as nee ded" basis, rather than continuously, by chreonic daily dosing.
According- to a first aspect of the present invention, new pharmaceutical compositions comprising an antidepressant are provid ed for treating premature ejaculatiomm by pulmonary inhalation.
This mode of administration preferably leads to the av-oidance of, or reduction in, side effects normally associated with the administration of the antdepressant. It ig especially poreferred that the compositions of the prese=nt invention have an extremely r=apid onset of the therapeutic effect, thereby allowing true "on demand” administration only a very short time before sexual actavity. The speed of onset of
‘ i v Rey -6- the therapeutic effect for the compositions of the present invention is discussed in greater detail below.
Antdepressants are drugs that relieve the symptoms of depression. T hey were first developed in the 1950s and have been used regularly since then. The so-called : tricyclic antidepressants (TCAs or TCADs) and the selective serotonin reuptake inhibitors (SSR1s) probably account for about 95% of antidepressan ®s prescribed.
The selecuve serotonin mand noradrenaline reuptake inhibitors (SNRs) are a newer group of antidepressants, but they are not yet so widely used.
Antidepressants are used to treat moderate to severe depressive llmesses. They are also used to help the symptoms of severe anxiety, panic attacks ancl obsessional problems. They fay also be used to help people with chronic pain, eating disorders and post-traumatic stress disorder. The mechanisms by which the various antidepressants are thought to work vary considerably between th ee various types of antidepressants.
There are a number o f different types of antidepressant drugs anc] these tend to fall into the following categories: 1) tricyclic antidepressants (TCADs or TCAs), such as clom3pramine, imipramine, lofepranmuine, nortriptyline, amitriptyline, desipramimme, dosulepin, doxepin, trimipramine, amoxapine, trazodone, amineptine, doth Jepin, iprindole, _ opipramol, propizep ine, protriptyline, quinupramine and fluphe mazine; 2) selective sercetonin and noradrenaline reuptake inhibitorss (SNR1s), such as venlafaxine and milsacipran; 3) selective serotonin reuptake inhibitors (SSRIs), such as «citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, clovoxamines, femoxetine, ifoxectine, viqualine zimeldine and sertraline; 4) selective noxadrenaline reuptake inhibitors (NARIs), somch as reboxetine, desipramine, oxapr-otiline and melitracen; 5) noradrenali ne and selective serotonin antidepressants CIN ASSAsS), such as sibutramine and fairtazapine;
. ® - 2006/Nn2747
We’ 0 2005/023550 : PCT/GB2004/003935 _7. 6). monoamine oxidase inhibitors (MAOIs), such as moclobemide, tra. nylcypromine, brofaromine, clorgyline, isocarbooxazid, nialamide, pirlindole, sel egiline, toloxatone, viloxazine and pbenelzineg 7) lithium salts, such as lithium carbonate aad Lithium citrate; 8) GABA potentators, such as valproic acid; 2) thioxanthenes, such as flupentxol; 10) teuacyclic antidepressants, such as mapreonline, levoprotiline, mianserin; and 11) further agents which may not fit into the above mentioned categories, such as bupropion, carbamazepine, tryptophan, ameseaigide, benactyzine, butniptyline, 70 ciAanopramine, demexiptiline, dibenzepin, dimeta crine, etoperidone, fezolamine, meecdifoxamine, metapramine, methylphenidate, rminaprine, nomifensine, oxaflozane, oxzitriptan, rolipram, setiptiline, teniloxazine, tiarmeptine, tofenacin and nefazodone.
Tle term antidepressants, as used herein, may al so encompass antipsychotic drugs 75 which may also be used in the compositions of the present invention. Such antipsychotic drugs include, for example, aripiprazole, chlorpromazine, zw clopenthixol, clozapine, flupentixol, sulpiride, perphenazine, fluphenazine, haloperidol, thioridazine, pericyazine, levomepromazine, pimozide, oxypertine, pipotazine, promazine, risperidone, quetiapine, amisulpride, trifluoperazine, pr-ochlorperazine, zotepine and olanzapine.
Amy of the abovementioned types or classes of antidepressants (for example, tri cyclic antidepressants) may be used in the present invention to treat PE. What is meore, any individual antidepressant mentioned above (for example, clomipramine) m=ay also be used to weat PE.
In one embodiment of the invention, the antidepressant included in the cosmposition is a tricyclic antidepressant. To vaxying extents, all of the absovementioned tricyclic agents share the capab-ility of inhibiting the neuronal uptake of norepinephrine. That said, these tricy-clic agents may vary in the severity of” their side effects, most notably in the degree of sedation and the extent of the am ticholinergic effects.
Clomipramine (3-chloro-5-{3-( dimethylamino)-propyl]-10,11-dihydro-5H- dibenz[b,f]azepine) is one of the preferred active agents used in the present invention. This tricyclic agent has both antidepressant and anti-obsessional , properues. Like other tricycliec antidepressants, clomipramine inhibits norepinephrine and serotonin uptake into central nerve terminals, possibly Yby : blocking the membrane-pump of neurons, thereby increasing the concentra tion of rapsmitter monoamines at re ceptor sites. Clomipramine is presumed to in fluence depression as well as obsessive and compulsive behaviour through its effects on serotonergic neurotransmissi=on. The actual neurochemical mechanism 1s numknown, .0 but clomipramine's capacity wo inhibit serotonin reuptake is thought to be important. Clomipramine als o appears also to have a mild sedative effect ~ovhich may be helpful in alleviating the anxiety component often accompanying depression.
As with other tricyclic compounds, clomipramine possesses anticholinergic properties which are respon sible for some of its side effects. It also has weak antihistamine and antiserotOnin properties, lowers the convulsive threshold, potentiates the effect of noxepinephiine and other drugs acting on the CNS, has a quinidine-like effect on the heart and may impair cardiac conduction.
Clomipramine is commercially available in the form of oral tablets or capsules, usually comprising 10,25, 50 or 75mg of clomipramine or clomipramine: hydrochloride. Absorption of clomipramine is reported to be rapid and complete after oral administration. Plasma levels usually peak some two hours afeer dosage but much individual variation occurs. The plasma half-life after a singles oral dose 1s approximately 21 hours, adthough the active metabolite desmethylclom ipramine has 2 half-life life of around 3 6 hours following oral administragon.
Whilst clomipramine has been shown to be effective in treating PE wi th oral doses starting from about 25mgs, the onset of the therapeutic effect of the dug is relatively slow and this does present problems and can destroy the spontaneity of sexual intercourse. Furthermore, doses of clomipramine of this magmitude are associated with a variety of side effects, most of which are mild, althc>ugh some of which can be serious.
On demand use of clomipramine to treat PE has beer suggested 1n US Patent No. 6.495,1 54. Although it is suggested in this patent that the drug may be administered less tha n 30 minutes prior to engaging in sexual activaty, there is actually no evidence provided to support this claim. There is als © no disclosure of a dosage form ox mode of administration which is likely to relmably and reproducibly provide such 2 xapid onset of the therapeutic effect in all pat cats.
It has mow been discovered that antidepressants are rapidly absorbed from the lung 70 and preovide an extremely rapid onset of their therapesutic effect. In fact, the onset of the therapeutc effect is significantly faster folowang pulmonary administration than that observed following oral administration of tablets and the like, even where the tabelets are formulated for fast release of the actiwe agent. 75 Additieonally, it has been found that the amount of amtidepressant required to treat sexual dysfuncuon when said dose is administered by pulmonary inhalation is significantly smaller than the doses provided by the currently available forms of anudegpressants, which are intended for oral administration.
What &s more, it has also been found that administeming antidepressants by pulmonary inhalation leads to an extremely benefici-al pharmacokinetic profile which provides an exceptionally fast onset of the therapeu tic effect with a short but suffici ent and suitable duration and subsequent fast elimination of the drug from the plasma. This is in contrast to the pharmacokinetics of the orally administered tablets which exhibit a relatively slow onset of the therapeutic effect and a long preserace of the drug in the plasma, presumably due to the more gradual absorption of the drug.
Advamtageously, it has also been found that the sm=zll dose of an antidepressant admimistered by pulmonary inhalation and the fast wonset and fast offset of the effect (provi ded by the rapid rise in drug plasma concentration, followed by the rapid fall thereof) observed as a result leads to a reduced incmdence of side effects generally associ ated with the administration of the drugs. M-ost anudepressants are associated
. } with relatively mild side eff ects, such as drowsiness, dry mouth, nausea, e=tc.. These side effects are generally thought to be dose-dependent, as well as being linked to chronic administration of t_he.antidepressants. Thus, these side effects may be ‘ reduced or avoided altogether as a result of the pulmonary administratio 1 of the antidepressants, as provide=d in the present inventon. . 1n accordance with anoihe=i aspect of the present invention, new metho «ds of treating premature ejaculation are provided, using new pharmaceutical compositions comprising an antidepress ant, wherein the compositions are administere=d by pulmonary inhalation.
Once again, these methods preferably achieve the desired therapeutic effect quickly, by virtue of a rapid onset of the effect of the antidepressant following pulmonary administration. Furthermore, the methods preferably also avoid or involve reduced 5s side effects that are normally or frequently associated with the adminisstration of the antidepressant, especially when they are administered orally.
According to one embodiment of the invention, the preferred antideperessant is a tricyclic antidepressant. In another embodiment, the tricyclic antidep ressant is clomipramine. The tern "clomipramine" as used herein includes clormipramine and clomipramine hydrochlo-ride, as well as any other derivatives of clom#pramine.
Other suitable tricyclic antidepressants include those mentioned abowze, such as imipramine, amiprityline= and doxepin.
The compositions of thes present invention may comprise two or mo xe different antidepressants, which rmay be from the same class or type of antidegpressant (such as two different tricyclic antidepressants) or from two or more different classes (such as one or more SSRIs and one or more MAOIs). What is mor-e, the compositions of the preesent invention can also additionally compris e other 10 therapeutic agents whicch may optionally assist the treatment of prermature ejaculation.
The additional therapeutc agents to be included in the compositions of the present inventon may be one or more of the following: 1) serotonin agonists, including 2-methyl serotonin, buspirone, ipsaperone, vaspirone, gepirone, lysergic acid diethylamide, ergot alkaloids, 8-hydroxy-(2-N,N-
dipropylamino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisaprnide, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride and mezacopride;
2) serotonin antagonists, including ondansetron, granisetron, metoclopramide, tropiseuon, dolasetron, trimethoben zamide, methysergide, risperidone, ketanserin,
70 ritanserin, clozapine, amiuryptline, R(+)-a-(2,3-dimethoxyphenyl)-1-{2-(4- fluorophenyl)ethyl}-4-pipenidin e-me thanol, azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine, chlorpromazine and mianserin;
3) adrenergic agonists, including methoxamine, methpentermine, metaraminol, mitodrine, clonidine, apraclonidine, guanfacine, guanabenz, methyldopa,
amphetamine, methamphetamine, epinephrine, norepinephrine, ethylnorepinephrine, phenylephrine, ephedrine, pseudoephedrine, methylphenidate, pemoline, naphazoline, tetrahydrozoline, oxymetazoline, xylometazoline, phenylpropanolamine, phenylethylarnine, dopamine, dobutamine, colterol, isoproterenol, isotharine, metaprotexenol, terbutaline, metaraminol, tyramine,
hydroxyamphetamine, ritodrine, premalterol, albuterol, 1soetharine, pirbuterol, bitolterol, fenoterol, formoterol, procaterol, salmeterol, mephenterine and propylbexedrine;
4) adrenergic antagonists, including phenoxybenzamine, phentolamine, tolazoline, prazosin, terazosin, doxa zosin, trimazosin, yohimbine, ergot alkaloids,
labetalol, ketanserin, urapidil, alfuzosin, bunazosin, tamsulosin, chlorpromazine, haloperidol, phenothiazines, butyrophenones, propranolol, nadolol, timolol, pindolol, metoprolol, atenolol, esmolol, acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, carvedilol, medroxalol, naftopidil, bucindolol, levobunolol, metipranolol, bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol, propafenone and indoramin; 5) adrenergic neurone blockers, including bethanidine, debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine, guanoclor and guanoxan; 6) benzodiazepines, including alprazolam, brouzolam, chlordiazepoxide,
h : clobazepam, clonazepam, clorazepate, dem oxepam, diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazapam, oxazepam, prazepam, quazcpaim, temazepam and triazolam; 7) neuroleptics, including chlorpromazine, uiflupromazine, mesondazine, thioridazine, acetophenazine, fluphenazine HC], perphenazine, prochlorperazine, wifluoroperazine, chlorprothizene, thiothixipe, haloperidol, loxapine, molindone, clozapine, rispcodonc, olanzapine and quetapme; 8) “alpha blockers, including prazosin, pbenoxybenzamine, doxazosin, terazosin, carvadilol and labetalol; 0 9) anxiolytics, including chlordiazpoxide, lorazepam and alprazolam; and 10) smooth muscle relaxants, including papaverine, phentolamige, clmetropium bromide, hyoscine butyl bromide, mebeverine, otilium bromide, pinaverium bromide, trimebutine and combinations thereof.
Particularly preferred additional active agents include benzodiazepines, such as those listed above.
The compositions and methods of the present invention provide a fast onset of the desired therapeutic effect. In particular, the onset is significantly faster than that observed upon oral zdministradon of antidepressants. In one embodiment of the invention, the onset of the therapeutic effect delaying ejaculation is less than 30 minutes from the administration of the composition via the pulmonary route. In other embodiments, the time from administration to onset of the therapeutic effect is no more than 25 minutes, no more than 20 minutes, no more than 15 minutes, no more than 10 minutes, no more than 8 minutes, no more than 6 minutes, no more than 5, 4, 3 or 2 minutes, or even no more than 1 minute.
The delay to onset of the therapeutic effect following pulmonary administration of the compositions of the present invention are significantly faster than the delays disclosed in the prior art, even where the prior art has referred to "rapid onset” an d "on demand" administration.
S13.
It is considered that, givesn the narure of the condiuon to be treated in the present invention, treatment canmot truly be said to be "on demand” unless the therapeutic effect provided by the composition 1s achieved within a period of less than 30 minutes, and really no more than 20 minutes. This is because maintaining the spontaneity of sexual intercourse plays a very important role in the treatment of PE, at the very least psychologically. Indeed, maintaining this spontaneity can even further assist the treatment of PE, beyond the effect of the antidepressant,
The present invention al so relates to high performance inhaled delivery of antidepressants, which h as a number of significant and unexpected advantages over oral administration. These advantages are discussed in greater detail below. It 1s the mode of administrat3on and the formulations of the present invention that make this excellent pexrforman ce possible. B
In accordance with one embodiment of the present invention, the pharmaceutical composition is in the foxm of a dry powder. Preferably, the dry powder is dispensed using a dry powder inhaler (DPI). :
In one embodiment of the present invention, the composition comprises active particles comprising an antidepressant, the active particles having a mass median aerodynamic diameter (IMMAD) of no more than about 10pm.
In another embodiment of the present invention, the composition comprises active particles comprising an antidepressant and an additive material which is an anti- adherent material and reduces cohesion between the particles in the composition.
In yet another embodiment of the present invention, the composition comprises active particles compris ing an antidepressant and carrier particles of an inert excipient material, such as lactose. The carrier particles may have an average i 30 particle size of from ab-out 5 to about 1000um.
In an alternative embodiment, the composition is a solution or suspension, which i's dispensed using a press urised metered dose inhaler (pMDI). The composition
Claims (1)
- ’ Ad 1/1 4 17 19 13 eemea— = A ——— =i * 1 i pd 1a 8. IN SE — s ” 12 / 18 14 i5 16 RyanxFig. 1 ! WAIN ; MIN) 1 }} ] J IR 1 IA NC 1 7 No) 1 0 ~ ~= 2 © g 7 Figure 2 a 2 —b ry Ens RENT I~ Res FREER or : = - Hyax ss 73 al fa a SEE oes 3 Figure 3
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0321612A GB0321612D0 (en) | 2003-09-15 | 2003-09-15 | Devices and pharmaceutical compositions for enhancing dosing efficiency |
Publications (1)
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ZA200602747B true ZA200602747B (en) | 2007-04-25 |
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ZA200602747A ZA200602747B (en) | 2003-09-15 | 2006-04-04 | Pharmaceutical compositions for treating premature ejaculation by pulmonary inhalation |
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CN (2) | CN1882318A (en) |
GB (1) | GB0321612D0 (en) |
ZA (1) | ZA200602747B (en) |
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MX2018001613A (en) * | 2015-08-14 | 2018-05-22 | Philip Morris Products Sa | A blister capsule, and container, for an aerosol-generating system. |
JP2021525571A (en) * | 2018-05-31 | 2021-09-27 | ベイポサーム, インコーポレイティド | Mechanical proximity spray inhaler |
CN109846841B (en) * | 2019-01-18 | 2021-06-01 | 西安力邦医药科技有限责任公司 | Quick-acting clobazam oral freeze-dried preparation and preparation method thereof |
-
2003
- 2003-09-15 GB GB0321612A patent/GB0321612D0/en not_active Ceased
-
2004
- 2004-09-15 CN CN 200480033670 patent/CN1882318A/en active Pending
- 2004-09-15 CN CNA200480033645XA patent/CN1882314A/en active Pending
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2006
- 2006-04-04 ZA ZA200602747A patent/ZA200602747B/en unknown
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CN1882318A (en) | 2006-12-20 |
CN1882314A (en) | 2006-12-20 |
GB0321612D0 (en) | 2003-10-15 |
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