[go: up one dir, main page]

WO1994009782A1 - Procedes et compositions de doxazosine (-) pour le traitement de l'hypertension - Google Patents

Procedes et compositions de doxazosine (-) pour le traitement de l'hypertension Download PDF

Info

Publication number
WO1994009782A1
WO1994009782A1 PCT/US1993/010504 US9310504W WO9409782A1 WO 1994009782 A1 WO1994009782 A1 WO 1994009782A1 US 9310504 W US9310504 W US 9310504W WO 9409782 A1 WO9409782 A1 WO 9409782A1
Authority
WO
WIPO (PCT)
Prior art keywords
doxazosin
amount
pharmaceutically acceptable
composition according
hypertension
Prior art date
Application number
PCT/US1993/010504
Other languages
English (en)
Inventor
Nancy M. Gray
Original Assignee
Sepracor, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sepracor, Inc. filed Critical Sepracor, Inc.
Priority to AU55462/94A priority Critical patent/AU5546294A/en
Publication of WO1994009782A1 publication Critical patent/WO1994009782A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines

Definitions

  • compositions of matter containing optically pure (-) doxazosin possess potent long lasting anti- hypertensive activity while avoiding adverse effects associated with the administration of the racemic mixture of doxazosin including but not limited to orthostatic hypotension, nausea, lethargy, fatigue and dizziness. Also disclosed are methods for treating hypertension in a human while avoiding adverse effects that are associated with the racemic mixture of doxazosin by administering the (-) isomer of doxazosin to said human.
  • the active compound of these compositions and methods is an optical isomer of doxazosin, which is described by Young and Brogden in Drugs 35. 525-541 (1988) and United States Patent No. 4,188,390. Chemically, the active compound is the (-) isomer of 4-amino-2-[4-(1,4-benzodioxan-2-carbony1)piperazin-1- yl]-6,7-dimethoxyquinazoline also known as l-(4- amino-6,7-dimethoxy-2-quinazolinyl)-4-[ (2,3-dihydro- 1,4-benzodioxan-2-yl)carbonyl]piperazine hereinafter referred to as doxazosin.
  • Doxazosin which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture. That is, (-) doxazosin is available only as a mixture of optical isomers, called enantiomers.
  • the racemic mixture of doxazosin is commercially available for administration as a methanesulfonate (mesylate) salt, but extensive pharmacology has been published on the hydrochloride salt as well.
  • D-lactic acid is the same as (-) lactic acid
  • L-lactic acid is (+)
  • stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoiso er may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
  • Doxazosin is a representative of a group of drugs that block ⁇ , adrenoceptors.
  • a ⁇ Receptors are innervated by postganglionic sympathetic neuronal fibers and are located in many body systems, including the cardiovascular system, where they are found primarily on smooth muscle cells in arterioles and venous capacitance vessels. Activation of these receptors by the physiological neurotrans itter substance, norepinephrine, increases peripheral arteriolar resistance and decreases venous capacitance.
  • Specific ⁇ , antagonists act to lower blood pressure and this is their primary current clinical indication.
  • ⁇ , antagonists such as phenoxybenzamine and phentolamine were not particularly useful as antihypertensive agents largely because of the substantial tachycardia which accompanied their use.
  • the tachycardic effect was however due primarily to the concomitant presynaptic ⁇ 2 receptor blocking activity of the early ⁇ antagonists. Inhibition of ⁇ 2 receptors acts presynaptically to augment the release of norepinephrine from adrenergic neurons. This stimulated the post-junctional sympathetic adrenoceptors in the heart which are predominately of the ⁇ adrenergic type. New, more specific, ⁇ receptor antagonists produce much less tachycardia than the older compounds.
  • vasodilation persists with the newer ⁇ antagonists, but the remaining tachycardia, renin release and increased cardiac output, which are all reflex mediated, return to normal.
  • ⁇ receptor inhibition
  • a troublesome cardiovascular problem related to the use of a 1 receptor antagonists is orthostatic hypotension. Symptomatic orthostatic hypotension is most likely to occur with high initial doses of ⁇ , antagonists or may occur when the dose is increased rapidly. A modest degree of fluid retention which is another result of vasodilation may also be observed when ⁇ , antagonists are used as single agents.
  • Doxazosin is a selective a x adrenergic receptor blocking agent structurally related to prazosin. Its oral bioavailability is good and the plasma half life in man is approximately 10 hours following both oral and intravenous administration.
  • Doxazosin has a single chiral center located on the carbon adjacent to the carboxyl group. This gives rise to a pair of enantio ers which have been resolved by Ley et al. rRecent Advances in Chiral Separations. Steven and Wilson Editors, Plenum Press, New York (1991) pages 97-103] on an analytical scale (0.52 ⁇ g) , but there are no reports in the literature of a preparative-scale separation of the enantiomers.
  • the racemic mixture of doxazosin is presently used primarily as an antihypertensive agent.
  • doxazosin leads to modestly decreased total cholesterol and LDL levels.
  • optically pure (-) isomer of doxazosin is an effective anti- hypertensive that avoids adverse effects associated with the administration of the racemic mixture, including but not limited to postural hypotension, nausea, lethargy, fatigue and dizziness.
  • the present invention also includes methods for treating hypertension in a human while avoiding the adverse effects that are associated with the racemic mixture of doxazosin, by administering the optically pure (-) isomer of doxazosin to said human.
  • the present invention encompasses a method of treating hypertension in a human, which comprises administering to a human in need of such antihypertensive therapy, an amount of (-) doxazosin, or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoiso er, said amount being sufficient to alleviate hypertension.
  • the method avoids the concomitant liability of adverse effects associated with the administration of racemic doxazosin by providing an amount of (-) doxazosin which is insufficient to cause the adverse effects associated with the racemic mixture of doxazosin.
  • the present invention also encompasses an antihypertensive composition for the treatment of a human in need of antihypertensive therapy, which comprises an amount of (-) doxazosin, or a pharmaceutically acceptable salt thereof, substantially free of its (+) stereoisomer, said amount being sufficient to alleviate said hypertension but insufficient to cause the adverse effects associated with racemic doxazosin.
  • the available racemic mixture of doxazosin i.e. a 1:1 racemic mixture of the two enantiomers
  • doxazosin possesses antihypertensive activity and provides therapy and a reduction of symptoms in conditions and disorders related to hypertension; however, this racemic mixture, while offering the expectation of efficacy, causes adverse effects.
  • Utilizing the substantially optically pure or optically pure isomer of doxazosin results in clearer dose related definitions of efficacy, diminished adverse effects, and accordingly, an improved therapeutic index. It is therefore more desirable to administer the (-) isomer of doxazosin than racemic doxazosin.
  • doxazosin includes, but is not limited to postural hypotension, nausea, lethargy, fatigue and dizziness.
  • Other side effects that have been reported with doxazosin include headache, blurred vision, edema, chest discomfort, constipation, dry mouth, sexual dysfunction, anxiety or nervousness, insomnia, palpitations, tachycardia, rash, paresthesia, muscle cramps, increased sweating, conjunctivitis, diarrhea, flatulence, dyspnea, neutropenia, leukopenia, rhinitis and increased frequency of micturition.
  • compositions contain a greater proportion of the (-) isomer of doxazosin in relation to the (+) isomer.
  • the term “substantially free of its (+) isomer” as used herein means that the composition is at least 90% by weight of (-) doxazosin and 10% by weight or less of (+) doxazosin.
  • the term “substantially free of the (+) stereoisomer” means that the composition contains at least 99% by weight of (-) doxazosin, and 1% or less of (+) doxazosin.
  • the term "substantially free of its (+) stereoisomer” as used herein means that the composition contains greater than 99% by weight of (-) doxazosin. These percentages are based upon the total amount of doxazosin in the composition.
  • the terms "substantially optically pure (-) isomer of doxazosin or "substantially optically pure (-) doxazosin” and “optically pure (-) isomer of doxazosin and “optically pure (-) doxazosin” are also encompassed by the above-described amounts.
  • the chemical synthesis of the racemic mixture of doxazosin can be performed by the method described in U.S. Patent 4,188,390.
  • the individual enantiomers of doxazosin may be obtained by resolution of the racemic mixture of enantiomers using conventional means.
  • the doxazosin may be resolved with an optically active acid such as tartaric acid at the N- (1,4-benzodioxan-2-carbony1)piperazine intermediate stage or at the final product.
  • the benzodioxan- carboxylic acid intermediate can be resolved with an optically active base such as brucine or ⁇ -phenethylamine.
  • Other standard methods of resolution known to those skilled in the art including but not limited to simple crystallization and chromatographic resolution, can be used.
  • optically pure (-) isomer can be prepared from the racemic mixture by enzymatic biocatalytic resolution. See for example, U.S. Patent Nos. 5,057,427 and 5,077,217, the disclosures of which are incorporated herein by reference.
  • the magnitude of a prophylactic or therapeutic dose of (-) doxazosin in the acute or chronic management of disease will vary with the severity of the condition to be treated, and the route of administration.
  • the dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient.
  • the total daily dose range, for (-) doxazosin, for the conditions described herein is from about 0.1 mg to about 20 mg, in single or divided doses.
  • a daily dose range should be between about 0.1 mg to about 10 mg, in single or divided doses, while most preferably, a daily dose range should be between about 0.5 mg to about 5 mg, in single or divided doses.
  • the therapy should be initiated at a lower dose, perhaps about 0.5 mg to about 1 mg, and increased up to about 8 mg or higher depending on the patient's global response. It is further recommended that children, and patients over 65 years, and those with impaired renal, or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The term "an amount sufficient to alleviate hypertension but insufficient to cause said adverse effects" is encompassed by the above-described dosage amounts and dose frequency schedule.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of (-) doxazosin.
  • oral, rectal, parentera1 (subcutaneous, intramuscular, intravenous) , transdermal, and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • compositions of the present invention comprise (-) doxazosin as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • salts or “a pharmaceutically acceptable salt thereof” refer to salts prepared from pharmaceutically acceptable non- toxic acids or bases including inorganic acids and bases and organic acids and bases. Since the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non- toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate) , benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, gluta ic, hydrobro ic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic (mesylate) , mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
  • compositions of the present invention include compositions such as suspensions, solutions, elixirs, aerosols, and solid dosage forms.
  • Carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, are commonly used in the case of oral solid preparations (such as powders, capsules, and tablets) , with the oral solid preparations being preferred over the oral liquid preparations.
  • the most preferred oral solid preparation is tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of the present invention may also be administered by controlled release means and/or delivery devices such as those described in U.S.Patent Nos. : 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719; the disclosures of which are hereby incorporated by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally, with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 0.5 mg to about 10 mg of the active ingredient.
  • the tablet, cachet or capsule contains either one of three dosages, about 0.5 mg, about 2 mg, or about 8 mg of the active ingredient.
  • Brain cortices are removed from male Wistar rats, and a membrane fraction is prepared (see Boyajian, C.L. and Leslie, F.M. J ⁇ _ Pharmacol. Exp. Ther. 241: 1092 - 1098, 1987).
  • the membrane preparation (10 mg) is incubated with 0.7 nM [ 3 H]-rauwolscine and varying concentrations of test substance for 30 minutes at 25° C.
  • Membranes are filtered and washed 3 times and the filters counted to determine the amount of [ 3 H]- rauwolscine specifically bound. Non-specific binding is determined by incubation with 1 ⁇ M yohimbine.
  • Groups of dogs are tested with suitable doses of racemic doxazosin, (-) doxazosin, and (+) doxazosin and the effects on blood pressure (orthostatic hypotension) and heart rate (reflex tachycardia) are monitored and recorded at predetermined time intervals.
  • Conscious normotensive dogs with surgically implanted arterial catheters are used to study the effects of the drugs on orthostatic hypotension and heart rate.
  • the animals may also be equipped with cutaneous electrodes connected to suitable equipment for recording electrocardiograms.
  • the tip of the indwelling catheter is positioned at the junction between the aorta and the left carotid artery.
  • Blood pressure is measured by means of a pressure transducer and heart rate is computed from the systolic peaks in blood pressure or from the R- waves of the EKG.
  • Doses of the test compounds are given orally or parenterally and the effects on the cardiovascular parameters are initially recorded with the animals in normal standing position. The animals are then held by their front paws and lifted into an upright position, standing on their hind paws. Drugs causing orthostatic hypotension will cause a sudden fall in recorded arterial blood pressure, sometimes accompanied by a reflex tachycardia.
  • the active ingredient, (-) doxazosin is sieved and blended with the excipients.
  • the mixture is filled into suitably sized two-piece hard gelatin capsules using suitable machinery.
  • Other doses may be prepared by altering the fill weight and if necessary, changing the capsule size to suit.
  • the active ingredient is blended with the lactose until a uniform blend is formed.
  • the smaller quantity of cornstarch is blended with the water to form the resulting cornstarch paste. This is then mixed with the uniform blend until a uniform wet mass is formed and the remaining cornstarch is added and mixed until uniform granules are obtained.
  • the granules are screened through a suitable milling machine using a 1/4" stainless steel screen. The milled granules are dried in a suitable drying oven and milled through a suitable milling machine again. The magnesium stearate is then blended and the resulting mixture is compressed into tablets of desired shape, thickness, hardness and disintegration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des procédés et compositions qui recourent à l'isomère (-) optiquement pur de la doxazosine. Ce composé constitue un médicament puissant qui permet de traiter l'hypertension tout en évitant les risques concomitants d'effets secondaires associés au mélange racémique de doxazosine.
PCT/US1993/010504 1992-11-04 1993-11-02 Procedes et compositions de doxazosine (-) pour le traitement de l'hypertension WO1994009782A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55462/94A AU5546294A (en) 1992-11-04 1993-11-02 Methods and compositions of (-) doxazosin for the treatment of hypertension

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97067392A 1992-11-04 1992-11-04
US07/970,673 1992-11-04

Publications (1)

Publication Number Publication Date
WO1994009782A1 true WO1994009782A1 (fr) 1994-05-11

Family

ID=25517299

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/010504 WO1994009782A1 (fr) 1992-11-04 1993-11-02 Procedes et compositions de doxazosine (-) pour le traitement de l'hypertension

Country Status (2)

Country Link
AU (1) AU5546294A (fr)
WO (1) WO1994009782A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260250A (zh) * 2005-11-11 2011-11-30 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅳ型结晶、其制备方法及用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4188390A (en) * 1977-11-05 1980-02-12 Pfizer Inc. Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4188390A (en) * 1977-11-05 1980-02-12 Pfizer Inc. Antihypertensive 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl) piperazin-1-yl or homopiperazin-1-yl]quinazolines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
G.W. LEY ET AL: "Optimisation of chiral separation of doxazosin enantiomers by high-performance liquid chromatography on a second generation alpha-1 acid glycoprotein column.", RECENT ADV. CHIRAL SEP., 1990, pages 97 - 103 *
J.L. POOL: "Plasma lipid lowering effects of doxazosin, a new selective alpha-1 adrenergic inhibitor for systemic hypertension.", AM. J. CARDIOL., vol. 59, no. 14, 1987, pages 46G - 50G *
R.A. YOUNG ET AL: "Doxazosin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in mild or moderate hypertension.", DRUGS, vol. 35, 1988, pages 525 - 541 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102260250A (zh) * 2005-11-11 2011-11-30 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅳ型结晶、其制备方法及用途
CN102260249A (zh) * 2005-11-11 2011-11-30 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅱ型结晶、其制备方法及用途
CN102321079A (zh) * 2005-11-11 2012-01-18 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅵ型结晶、其制备方法及用途
CN102321079B (zh) * 2005-11-11 2013-08-28 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐vi型结晶、其制备方法及用途
CN102321078B (zh) * 2005-11-11 2013-08-28 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐iii型结晶、其制备方法及用途
CN102321080B (zh) * 2005-11-11 2013-09-25 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐v型结晶、其制备方法及用途
CN102260250B (zh) * 2005-11-11 2013-09-25 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅳ型结晶、其制备方法及用途
CN102260249B (zh) * 2005-11-11 2013-11-13 华北制药集团新药研究开发有限责任公司 (-)多沙唑嗪甲磺酸盐ⅱ型结晶、其制备方法及用途

Also Published As

Publication number Publication date
AU5546294A (en) 1994-05-24

Similar Documents

Publication Publication Date Title
US6291490B1 (en) Methods and compositions for treating conditions caused by excessive calcium influx in cells using optically pure (-) amlodipine
WO1994006429A1 (fr) Compositions pour traiter des affections allergiques a l'aide de (-) cetirizine
AU3147593A (en) Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine
US5508279A (en) Methods and compositions of (+) doxazosin for the treatment of benign prostatic hyperplasia
US5510352A (en) Methods of using (+) doxazosin for the treatment of hypertension
US5834496A (en) Methods for treating hypertension using optically pure S(-) felodipine
WO1994009782A1 (fr) Procedes et compositions de doxazosine (-) pour le traitement de l'hypertension
WO1994009783A1 (fr) Procedes et compositions contenant de la doxazosine (-) utilises dans le traitement de l'adenome prostatique et de l'atherosclerose
US5571827A (en) Methods and compositions for treating hypertension, angina and other disorders using optically pure s(-) nitrendipine
AU724714B2 (en) Methods and compositions of (+) doxazosin for the treatment of hypertension and benign prostatic hyperplasia
CA2125149A1 (fr) Methodes et compositions pour le traitement de l'hypertension, de l'angor et d'autres affections par l'administration de s(-)felodipine optiquement pure
EP0663822A1 (fr) Procedes et compositions permettant de traiter l'hypertenson, les angines et d'autres affections au moyen de nitredipine s(-) optiquement pure
EP1614420A2 (fr) Traitment de l'hypertension, de l'angine de poitrine et d'autres troubles avec (-)amlodipine
HK1029521A (en) Method and compositions for treating hypertensioin, angina and other disorders using optically pure (-) amlodipine.
AU2006200150A1 (en) Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine
AU1354000A (en) Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR BY CA CH CZ DE DK ES FI GB HU JP KP KR KZ LK LU LV MG MN MW NL NO NZ PL PT RO RU SD SE SK UA UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA