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The British MHRA (Medicines and Healthcare Products Regulatory Agency) has published a guidance for developers of “software as a medical device” = “stand-alone software”. The text also expressly addresses “apps”. Get the details here.

http://www.gmp-compliance.org/enews_4445_MHRA-s-Guidance-for-Software-as-a-Medical-Device–including-Apps-_8308,8394,9058,9051,Z-COVM_n.html

Whereas in the pharmaceutical business software plays a role in the manufacture of products, it can also act as two parts in the medical device business – one in the manufacture of a device and one as a medical device as such – i.e. software as a medical device. The British Health Authority – MHRA – has published a current guidance on software as a medical device, also called stand-alone software, intended for developers of such software. This guidance also addresses the increasingly encountered topic “apps”. The text doesn’t cover software that is part of a medical device, e.g. software that controls a CT scanner.

The guidance itself is very short and divided into 6 main chapters:

Introduction
Key points and existing…

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Questions and Answers on the Topic “Pharmaceutical Water”

September 6, 2014 2:55 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

In the following News, you will find questions on pharmaceutical water preparation and distribution frequently asked during our courses, as well as their respective answers. Read more here.

http://www.gmp-compliance.org/enews_4422_Questions-and-Answers-on-the-Topic-%22Pharmaceutical-Water%22_8398,8427,8428,8526,Z-PEM_n.html

During our courses and conferences participants quite frequently raise questions on pharmaceutical water preparation and distribution. Therefore following you will find some of these questions and their respective answers.

Question 1: Which concentrations of ozone are required in water systems?

The technical literature delivers different information about the ozone concentrations in water systems: e.g. ISPE Baseline Water and Steam: 0.02 ppm – 0.2 ppm; Collentro, Pharmaceutical Water: 0.2 ppm – 0.5 ppm and W.Setz, Ciba-Geigy 1990: max 0.04 ppm, for sanitisation 0.05 ppm.
The indications provided by the ISPE Baseline refer to the concentration required to prevent microbial growth. One can thus assume that a concentration of 20 ppb ozone can prevent any growth.

If systemic protection is desired i.e. the…

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EU Commission publishes long-awaited EU GMP Guide Chapters 3 and 5

September 6, 2014 2:51 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The EU Commission has published the long-awaited, revised chapters 3 and 5 of the EU GMP Guide. The change focuses on the prevention of cross-contamination as well as on the statement concerning the need for dedicated facilities. Continue reading.

http://www.gmp-compliance.org/enews_4499_EU-Commission-publishes-long-awaited-EU-GMP-Guide-Chapters-3-and-5_9086,8427,8526,Z-PEM_n.html

The EU Commission had published its first draft of the chapter 3 “Premises and Equipment” and 5 “Production” for comments in early 2013 (see news from 04/12/2013). The content concerns the measures for avoiding cross-contamination and the regulation relative to which products have to be produced in dedicated facilities.

The mention of specific products for which a dedication is required – as provided in the currently valid version of chapter 3 – is missing in the now published version. The quality risk management approach is maintained. Also remaining are the exceptions where dedication is required – which are:

The risk cannot be adequately controlled by operational and/ or technical measures…

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AMRI Introduces Protein Expression & Purification Solutions

September 5, 2014 11:30 am / Leave a comment

A MESSAGE FROM MICHAEL A. LUTHER, SENIOR VICE PRESIDENT DISCOVERY AND DEVELOPMENT

Dear Anthony,As a company with a deep history of discovery innovation, Albany Molecular Research Inc. (AMRI) continues to explore scientific solutions that provide our customers with enhanced flexibility and access to state-of-the-art science and technologies. As part of our aim to provide you with high-value services in the area of biology and pharmacology, today we announced new platforms that enhance our discovery biology offerings.One of our new platforms comprises IND-enabling support services, which are aimed at supporting the successful initiation and completion of customer Investigational New Drug (IND) programs. As part of this offering we now provide in vitro DMPK studies, related to drug-drug interactions and metabolism, which are routinely included in IND submissions. Our Drug Metabolism and Pharmacokinetics (DMPK) group provides in vitro DMPK and bioanalytical/PK services as part of our Drug Discovery and Development Solutions (DDS) business. These services span all stages of drug discovery including exploratory, hit-to-lead, lead optimization and candidate selection, as well as the pre-clinical IND-enabling stage.More recently, we have expanded into the protein market with an initial focus on protein expression and purification. As part of a public-private pharmaceutical research and development initiative in Buffalo, N.Y., our current and ongoing activities encompass the production of purified recombinant proteins as reagents and tools for biological assays and sterile, pyrogen-free materials for proof-of-concept, non-human in vivo studies. We are very excited to be able to offer these expanded biology services as we continue to seek innovative ways to provide relevant drug discovery services and expertise to academia and the global Bio-Pharmaceutical industry from early discovery to candidate selection and beyond.

Our goal is to leverage our deep expertise to provide you with high quality and innovative scientific solutions that drive your pipeline and portfolio. As always, if you have questions about any of the services we can provide, please contact us to request a quote so we can discuss your needs.

Sincerely,

Michael A. Luther, Ph.D., MBA
Senior Vice President, Discovery and Development
Albany Molecular Research Inc. (AMRI)

Albany Molecular Research Inc. (AMRI)
26 Corporate Circle
Albany, NY 12203

21′α-Cyanoanhydrovinblastine

September 5, 2014 11:28 am / Leave a comment

Some derivatives ) are known as being intermediates in the preparation of anti-tumor medicaments such as vinblastine, vincristine and vinorelbine.

R=CH₃, vinblastine

R=CHO, vincristine

n=2, anhydrovinblastine

n=1, vinorelbine

The remarkable anti-tumor properties of these complex natural molecules, extracted from the Madagascar periwinkle, Carantheus roseus, are known and they are already used in anti-cancer treatment. Vinblastine and vincristine are “spindle poisons” which oppose the formation of the mitotic spindle during cellular division, thus preventing cellular proliferation.

Vincristine and vinblastine are active agents in the treatment of leukemia, lymphosarcoma and solid tumors. Vinblastine is also used in the treatment of Hodgkin’s disease.

Vinorelbine is currently used in the treatment of the most widespread form of cancer of the lungs, that is lung cancer of non-small cells. It is also used in the treatment of metastasic cancers of the breast.

The methods currently used for preparing vinblastine and vincristine involve extraction of these molecules from plants. The plants have to be crushed and dried before these substances can be extracted. The extraction process is long and costly, given that the extract obtained is very complex, containing at least 200 different alkaloids. The yields are also very low; 5 to 10 g of vinoblastine are obtained per ton of dried plant material, and 0.5 to 1 g of vincristine per ton of dried plant material.

Many research groups have thus tried to achieve synthesis of these molecules by using more efficient procedures which enable better yields and which make use of derivatives with interesting anti-tumor properties but which are endowed with lower levels of toxicity.

just an animation

The patent FI 882 755, filed by the HUATAN-MAKI Oy Company, relates to the formation of vinblastine and vincristine by irradiation of catharanthine and of vindoline with UV radiation in an acidic aqueous solution, under an atmosphere of oxygen or an inert gas. The yields obtained in these reactions are extremely low.

Furthermore, other processes are known which make use of anhydrovinblastine which is an intermediate in the synthesis of vinblastine, vincristine and also of vinorelbine.

Anhydrovinblastine is thus a key chemical intermediate which enables access to all alkaloids of the vinblastine type. This intermediate is synthesised by coupling catharanthine and vindoline.

The latter two alkaloids are also extracted from the Madagascar periwinkle but, in contrast to vincristine and vinblastine, they represent the main constituents of the extract obtained. In fact, 400 g of catharanthine per ton of dried plant material and 800 g of vindoline per ton of dried plant material are obtained.

The preparation of anhydrovinblastine by coupling catharanthine and vindoline is therefore a favoured route for synthesising this intermediate product.

There are several methods for preparing anhydrovinblastine from catharanthine and vindoline.

The patent FR 2 296 418 filed by ANVAR describes a process during the course of which the N-oxide of catharanthine is coupled to vindoline in the presence of trifluoroacetic anhydride.

When this process is performed at ambient temperature only the inactive 16′-R epimer of anhydrovinblastine is obtained. The naturally occurring active 16′-S epimer is obtained as the major product when this reaction is performed at a temperature which is at least 50° C. lower and under an inert gas. Nevertheless, even at low temperature, 10% of the 16′-R epimer of anhydrovinblastine is still produced.

This process has several disadvantages. The operating conditions are extremely restrictive due to the use of anhydrous solvents, the low temperature and the atmosphere of inert gas. The product obtained has to be subjected to a purification procedure due to the presence of 10% of the 16′-R epimer of anhydrovinblastine. The yield of isolated anhydrovinblastine is low, of the order of 35%.

A second process, suggested by VUKOVIC et al. in the review “Tetrahedron” (1998, volume 44, pages 325-331) describes a coupling reaction between catharanthine and vindoline initiated by ferric ions. Catharanthine is also oxidised in this reaction. The yield of anhydrovinblastine is of the order of 69% when the reaction is performed under an atmosphere of inert gas. However, this process has the major disadvantage that it leads to many secondary products. These are impurities resulting from further oxidation of the dimeric alkaloids formed, whatever the chosen operating conditions. This makes the purification stage difficult and delicate.

An improved process was suggested in the patent U.S. Pat. No. 5,037,977 and this increases the yield of anhydrovinblastine to 89%. However, this improvement is described only for very small amounts of reagents and its extension to the industrial scale seems to be difficult. In any case, these processes based on ferric ions lead in all cases to many secondary products due to the fact that these ions are responsible for parasitic reactions.

A third process described by GUNIC et al. in “Journal of the Chemical Society Chemical Communications” (1993), volume 19, pages 1496-1497, and by Tabakovic et al. in “Journal of Organic Chemistry” (1997), volume 62, pages 947-953, describes a coupling reaction between catharanthine and vindoline as a result of anodic oxidation of catharanthine. However, this process also suffers from disadvantages which, on the one hand, are due to the requirement for an inert atmosphere and, on the other hand, are connected with the nature of the electrochemical process itself, involving wear of the electrodes, difficulty in controlling the reproducibility and the cost of electrolytes. And, as in all the preceding methods, the anhydrovinblastine is contaminated with about 10% of the 16′-R epimer of anhydrovinblastine.

http://www.google.com/patents/US6365735

EXAMPLE 11 Preparation of 21′α-Cyanoanhydrovinblastine

0.537 mmol of catharanthine hydrochloride (200 mg), 0.537 mmol of vindoline (245 mg) and 0.054 mmol of dimethyl viologen (14 mg) and 0.028 mmol of triphenylpyrilium hydrogen sulfate (11 mg) are added to 50 ml of 0.1 N sulfuric acid. The entire mixture is irradiated with light of wavelength λ>400 nm in a Pyrex irradiation flask, under an atmosphere of oxygen. The reaction is terminated after 2 h 30 min of irradiation.

The aqueous phase is then saturated with lithium tetrafluoroborate and then extracted with dichloromethane. A solution of 15 ml of dichloromethane containing 100 μl (1.34 mmol, 2 eq.) of trimethylsilyl cyanide, TMSCN, is then added to the reaction medium. The organic phase is washed with a solution of 0.1 M sodium carbonate, dried and evaporated under reduced pressure at 20° C.

The only product in the residue (403 mg, 0.509 mmol, 95%) is recrystallised from absolute isopropanol. 340 mg of white crystals of 21′α-cyanoanhydrovinblastine (0.430 mmol; yield: 80%) are recovered.

C₄₇H₅₅N₅O₈

M.pt. 212° C. (iPrOH) IR film 3450, 2950, 2220, 1740, 1610 cm⁻¹; MS M/z (relative intensity) 818 (MH+, 3), 122 (100), 108 (21);

NMR ¹H (500 MHz, CDCl3) 9.78 (s, 1H, OH), 8.04 (s, 1H, Na′H), 7.51 (1H, H-9′), 7.16 (1H, H-11′), 7.13 (1H, H-12′), 7.12 (1H, H-10′), 6.63 (s, 1H, H-9), 6.13 (s, 1H, H-12), 5.85 (m, 1H, H-14), 5.47 (s, 1H, H_α-17), 5.54 (m, 1H, H-15′), 5.30 (m 1H, H-15), 4.18 (1H, H₆₂-2), 3.60 (s, 3H, C16′—COOCH₃), 3.38 (1H, H₆₂-3), 3.35 (1H, H_β-3′), 3.31 (1H, H_β-5), 3.25 (1H, H_β-6′), 3.24 (m, 1H, H_β-5′), 3.15 (1H, H_β-17′), 3.14 (m, 1H, H_α-5′), 3.12 (1H, H_α-6′), 2.82 (1H, H_α-3), 2.72 (s, 3H, NaCH₃), 2.66 (s, 1H, H_α-21), 2.62 (1H, H_α-3′), 2.46 (1H, H_α-5), 2.40 (1H, H_α-17′), 2.20 (1H, H_β-5), 2.11 (s, 3H, CH₃—COO), 2.11 (1H, H-19′), 2.03 (1H, H-19′), 1.80 (1H, H_α-6), 1.80 (1H, H-19), 1.35 (1H, H-19), 1.21 (m, 1H, H-14′), 1.04 (3H, H-18′), 0.81 (3H, H-18).

NMR ¹³C (125 MHz, CDCl3) 174.69 (C_16′—COOCH₃), 171.74 (C₁₆—COOCH₃), 171.03130.01 (C₁₅), 129.34 (C_8′),129.16 (C_15′), 124.63 (C₁₄), 123.48 (C₉), 123.24 (C₈), 122.49 (C_11′), 121.00 (C₁₀), 119.21 (C_10′), 119.21 (CN), 118.35 (C_9′), 115.65 (C_7′), 110.64 (C₁₁—OCH₃), 55.40 (C_16′), 53.30 (C₇), 52.46 (C_16′—COOCH₃), 52.30 (C₁₆—COOCH₃), 52.26 (C_5′), 50.50 (C₅), 50.41 (C₅), 44.86 (C₆), 44.48 (C_3′), 42.76 (C₂₀), 38.32 (Na—CH₃), 34.00 (C_17′), 33.28 (C_14′), 30.92 (C₁₉), 28.63 (C_8′), 25.92 (C_19′), 21.19 (CH₃—COO), 11.86 (C_18′), 8.50 (C₁₈).

Patent Citations

Cited Patent	Filing date	Publication date	Applicant	Title
US4737586	Apr 29, 1986	Apr 12, 1988	Agence Nationale De Valorisation De La Recherche	Process for the preparation of bis-indolic compounds
US5037977	Aug 8, 1989	Aug 6, 1991	Mitsui Petrochemical Industries Ltd.	Reacting catharanthine with vindoline in presence of ferric ions, inactivating iron with ligand, reducing
DE3801450A1	Jan 20, 1988	Aug 18, 1988	Univ British Columbia	Verfahren fuer die synthese von vinblastin und vincristin
DE3826412A1	Aug 3, 1988	Feb 16, 1989	Univ British Columbia	Verfahren fuer die synthese von vinblastin und vincristin
WO1989012056A1	Jun 9, 1989	Dec 14, 1989	Huhtamaeki Oy	Process for the preparation of dimeric catharanthus alkaloids

Non-Patent Citations

Reference
1		E. Gunic et al., “Electrochemical Synthesis of Anhydrovinblastine“, J. Chem. Soc., Chem. Commun., 1993, pp. 1496-1497.
2		I. Tabakovic et al., “Anodic Fragmentation of Catharanthine and Coupling with Vindoline. Formation of Anhydrovinblastine“, J. Org. Chem., 1997, vol. 62, pp 947-953.
3		J. Vucovik et al., “Production of 3′,4′-anhydrovinblastine: a Unique Chemical Synthesis“, Pergamon Journals Ltd., 1988, vol. 44, pp. 325-331.
4		Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,-Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB-the whole document.
5		Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,-Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US -the whole document.
6		Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB-the whole document.
7		Richard J. Sundberg et al.; “Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates” Tetrahedron., vol. 48, No. 2,—Jan. 10, 1992; pp. 277-296, XP002083507 Oxford GB—the whole document.
8		Richard J. Sundberg et al.; “Oxidative fragmentation of catharanthine by dichlorodicyanoquinone“; Journal of Organic Chemistry,—Mar. 1, 1991; pp. 1689-1692, XP002083508 Easton US —the whole document.
9		Richard J. Sundberg et al.; “Photoactivated C16-C21 fragmentation of catharanthine” Tetrahedron Letters, vol. 32, No. 26, Jun. 24, 1992, pp. 3035-3038 XP002083509 Oxford GB—the whole document.

Citing Patent	Filing date	Publication date	Applicant	Title
US7235564 *	Dec 3, 2004	Jun 26, 2007	Amr Technology, Inc.	11′-substituted; potent inhibitors of cellular mitosis and proliferation
US7238704 *	Dec 3, 2004	Jul 3, 2007	Amr Technology, Inc.	For use as inhibitors of cellular mitosis and proliferation
US7745619	Oct 31, 2007	Jun 29, 2010	Albany Molecular Research, Inc.	alkaloids; anticarcinogenic, antiproliferative agent; inhibitor of cellular mitosis and cell proliferation; binding to tubulin leads to cell cycle arrest in M phase and subsequently to apoptosis; antiallergen, antiinflammatory, antidiabetic, autoimmune diseases; asthma, arthritis, Alzheimer’ disease
US7842802	Dec 10, 2008	Nov 30, 2010	Albany Molecular Research, Inc.	Vinorelbine derivatives
US8048872	Apr 29, 2008	Nov 1, 2011	Stat of Oregon Acting by and Through The Oregon State Board of Higher Education on Behalf of the University of Oregon	Treatment of hyperproliferative diseases with vinca alkaloid N-oxide and analogs
US8053428	Apr 6, 2007	Nov 8, 2011	Albany Molecular Research, Inc.	Vinorelbine derivatives
WO2005055939A2*	Dec 3, 2004	Jun 23, 2005	Amr Technology Inc	Vinca derivatives

Acebutolol……..For the management of hypertension and ventricular premature beats in adults.

September 5, 2014 11:25 am / Leave a comment

Acebutolol

N-(3-Acetyl-4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl)butanamide

3′-acetyl-4′-(2-hydroxy-3-(isopropylamino)propoxy)butyranilide

(±)-acebutolol

Acetobutolol; Sectral; Prent; Neptal; Acebutololum; Acebutololo; (+-)-Acebutolol; dl-Acebutolol; Acebrutololum

Molecular Formula: C₁₈H₂₈N₂O₄ Molecular Weight: 336.42592

CAS Registry Number: 37517-30-9

CAS Name: N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl]butanamide

Additional Names: 3¢-acetyl-4¢-[2-hydroxy-3-(isopropylamino)propoxy]butyranilide; 1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane; 5¢-butyramido-2¢-(2-hydroxy-3-isopropylaminopropoxy)acetophenone

Percent Composition: C 64.26%, H 8.39%, N 8.33%, O 19.02%

Melting point: mp 119-123°

Derivative Type: Hydrochloride

CAS Registry Number: 34381-68-5

Manufacturers’ Codes: M & B 17803A; IL-17803A

Trademarks: Acecor (SPA); Acetanol (RPR); Neptal (Procter & Gamble); Prent (Bayer); Sectral (RPR)

Molecular Formula: C18H28N2O4.HCl

Molecular Weight: 372.89

Percent Composition: C 57.98%, H 7.84%, N 7.51%, O 17.16%, Cl 9.51%

Properties: Crystals from anhydr methanol-anhydr diethyl ether, mp 141-143°. Freely sol in water. Soly at room temperature (mg/ml): water 200; ethanol 70.

Melting point: mp 141-143°

Therap-Cat: Antihypertensive; antianginal; antiarrhythmic (class II).

Acebutolol (trade names Sectral, Prent) is a beta blocker for the treatment of hypertension and arrhythmias.

A cardioselective beta-adrenergic antagonist with little effect on the bronchial receptors. The drug has stabilizing and quinidine-like effects on cardiac rhythm as well as weak inherent sympathomimetic action.

View current batch: S401001..http://www.selleckchem.com/products/acebutolol-hcl.html

Purity=99.93% COA

Brief background information

Salt	ATC	Formula	MM	CAS
–	C07AB04 C07BB04	C ₁₈ H ₂₈ N ₂ O ₄	336.43 g / mol	37517-30-9
(R) be the bases	C07AB04 C07BB04	C ₁₈ H ₂₈ N ₂ O ₄	336.43 g / mol	68107-81-3
(S) be the bases	C07AB04 C07BB04	C ₁₈ H ₂₈ N ₂ O ₄	336.43 g / mol	68107-82-4
(RS) -monogidrohlorid	C07AB04 C07BB04	C ₁₈ H ₂₈ N ₂ O ₄ · HCl	372.89 g / mol	34381-68-5

Acebutolol
Systematic (IUPAC) name


(RS)-N-{3-acetyl-4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl}butanamide
Clinical data
Trade names	Sectral
AHFS/Drugs.com	monograph
MedlinePlus	a687003
Licence data	US FDA:link
Pregnancy cat.	C (AU) B (US)
Legal status	℞ Prescription only
Routes	oral, iv
Pharmacokinetic data
Bioavailability	40% (range 35 to 50%)
Metabolism	Hepatic
Half-life	3-4 hours (parent drug) 8-13 hours (active metabolite)
Excretion	Renal: 30% Biliary: 60%
Identifiers
CAS number	37517-30-9
ATC code	C07 AB04
PubChem	CID 1978
DrugBank	DB01193
ChemSpider	1901
UNII	67P356D8GH
KEGG	D02338
ChEBI	CHEBI:2379
ChEMBL	CHEMBL642
Chemical data
Formula	C₁₈H₂₈N₂O₄
Mol. mass	336.426 g/mol


Physical data
Melt. point	121 °C (250 °F)

Application

antagonist of β-adrenergic
β-blocker

Classes of substances

Acetophenones
- 1-aryloxy-3-amino-2-propanol
  - Butyric acid anilides

Synthesis pathway

Chemical structure for Acebutolol

Synthesis a)

Trade Names

Country	Trade name	Manufacturer
Germany	Printemps	Bayer
	Sali-Printemps	– “-
	Tredalat	– “-
France	Sektral	Sanofi-Aventis
United Kingdom	Sekadreks	Aventis
United Kingdom	Sektral	Aventis
Italy	Atsekor	SPA
	AlOl	SIT
	Printemps	Bayropharm
	Sektral	Rhône-Poulenc Rorer
Japan	Atsetanol	Sanofi-Aventis Chugai
Japan	Sektral	Organon
USA	– “-	Wyeth-Ayerst
Ukraine	No	No

Formulations

ampoule 25 mg;
Capsules 100 mg, 200 mg;
Tablets of 200 mg, 400 mg, 500 mg (as hydrochloride)

Pharmacology

Acebutolol is a cardioselective beta blocker with ISA (intrinsic sympathomimetic activity; see article on pindolol). It is therefore more suitable than non cardioselective beta blockers, if a patient with asthma or chronic obstructive pulmonary disease (COPD) needs treatment with a beta blocker. (For these reasons, it may be a beta-blocker of choice in inclusion in Polypill strategies). In doses lower than 800mg daily its constricting effects on the bronchial system and smooth muscle vessels are only 10% to 30% of those observed under propranolol treatment, but there is experimental evidence that the cardioselective properties diminish at doses of 800mg/day or more.

The drug has lipophilic properties, and therefore crosses the blood–brain barrier. Acebutolol has no negative impact on serum lipids (cholesterol and triglycerides). No HDL decrease has been observed. In this regard, it is unlike many other beta blockers which have this unfavourable property.

The drug works in hypertensive patients with high, normal, or low renin plasma concentrations, although acebutolol may be more efficient in patients with high or normal renin plasma concentrations. In clinically relevant concentrations, a membrane-stabilizing effect does not appear to play an important role.

Pharmacokinetics

Acebutolol is well absorbed from the GI tract, but undergoes substantial first-pass-metabolization, leading to a bioavailability of only 35% to 50%. Peak plasma levels of acebutolol are reached within 2 to 2.5 hours after oral dosing. Peak levels of the main active metabolite, diacetolol, are reached after 4 hours. Acebutolol has a half-life of 3 to 4 hours, and diacetolol a half-life of 8 to 13 hours.

Acebutolol undergoes extensive hepatic metabolization resulting in the desbutyl amine acetolol which is readily converted into diacetolol. Diacetolol is as active as acebutolol (equipotency) and appears to have the same pharmacologic profile. Geriatric patients tend to have higher peak plasma levels of both acebutolol and diacetolol and a slightly prolonged excretion. Excretion is substantially prolonged in patients with renal impairment, and so a dose reduction may be needed. Liver cirrhosis does not seem to alter the pharmacokinetic profile of the parent drug and metabolite.

Indications

hypertension
ventricular and atrial cardiac arrhythmia
acute myocardial infarction in high-risk patients
Smith-Magenis syndrome

Contraindications

Stable or Unstable Angina (due to its partial agonist or ISA activity)

Contraindications and Precautions

Further information: Propranolol

Acebutolol may not be suitable in patients with Asthma bronchiale or COPD due to its bronchoconstricting (β2 antagonistic) effects.

Side effects

Further information: Propranolol

The development of anti-nuclear antibodies (ANA) has been found in 10 to 30% of patients under treatment with acebutolol. A systemic disease with arthralgic pain and myalgias has been observed in 1%. A lupus erythematosus-like syndrome with skin rash and multiforme organ involvement is even less frequent. The incidence of both ANA and symptomatic disease under acebutolol is higher than under Propranolol. Female patients are more likely to develop these symptoms than male patients. Some few cases of hepatotoxicity with increased liver enzymes (ALT, AST) have been seen. Altogether, 5 to 6% of all patients treated have to discontinue acebutolol due to intolerable side effects. When possible, the treatment should be discontinued gradually in order to avoid a withdrawal syndrome with increased frequency of angina and even precipitation of myocardial infarction.

Dosage

The daily dose is 200mg – 1,200mg in a single dose or in 2 divided doses as dictated by the severity of the condition to be treated. Treatment should be initiated with low doses, and the dose should be increased cautiously according to the response of the patient. Acebutolol is particularly suitable for antihypertensive combination treatment with diuretics, if acebutolol alone proves insufficient. In some countries injectable forms for i.v.-injection with 25mg acebutolol exist, but these are only for cases of emergency under strict clinical monitoring. The initial dose is 12.5 to 25mg, but additional doses may be increased to 75 to 100mg, if needed. If further treatment is required, it should be oral.

Sectral (acebutolol HCl) structural formula illustration

Sectral (acebutolol HCl) is a selective, hydrophilic beta-adrenoreceptor blocking agent with mild intrinsic sympathomimetic activity for use in treating patients with hypertension and ventricular arrhythmias. It is marketed incapsule form for oral administration. Sectral (acebutolol) capsules are provided in two dosage strengths which contain 200 or 400 mg of acebutolol as the hydrochloride salt. The inactive ingredients present are D&C Red 22, FD&C Blue 1, FD&C Yellow 6, gelatin, povidone, starch, stearic acid, and titanium dioxide. The 200 mg dosage strength also contains D&C Red 28 and the 400 mg dosage strength also contains FD&C Red 40. Acebutolol HCl has the following structural formula:

Acebutolol HCl is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±)N-[3-Acetyl-4-[2- hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide.

External links

AHFS Database

see DrugSyn.org

US3857952

http://www.google.co.in/patents/US3857952

EXAMPLE 5 5-Butyramido-2-(2-hydroxy-3-isopropylaminopropoxy)acetophenone (3.36 g.; prepared as described in Example (4) was dissolved in anhydrous methanol (50 ml.), and anhydrous diethyl ether (200 ml.) added. A saturated solution of anhydrous hydrogen chloride in anhydrous diethyl ether (25 ml.) was added dropwise with stirring. An oil was precipitated, which crystallized on further stirring. The solid was filtered off and recrystallized from a mixture of anhydrous methanol and anhydrous diethyl ether to give 5-butyramido-2′-(2- hydroxy-3-isopropyl’amino-propoxy)acetophenone hydrochloride (2.5 g.), m.p. l4ll43C.

EXAMPLE 4 Crude 5-butyramido-2′-(2,3-epoxypropoxy)acetophenone (16 g), isopropylamine (20 g.) and ethanol (100 ml.) were heated together under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure and theresidual oil was dissolved in N hydrochloric acid. The acid solution was extracted with ethyl acetate, theethyl acetate layers being discarded. The acidic solution was brought to pH 11 with 2N aqueous sodium hydroxide solution and then extracted with chloroform. The dried chloroform extracts were concentrated under reduced pressure to give an oil which was crystallised from a mixture of ethanol and diethyl ether to give 5′-butyramido-2- (2-hydroxy-3-isopropylaminopropoxy)acetophenone (3 g.), m.p. 119l23C.

Similarly prepared was cyclohexylamino-2-hydroxypropoxy)acetophenone, m.p. 112113C.

Crude 5-butyramido-2-(2,3-epoxypropoxy)acetophenone used as startingmaterial was prepared as follows:

p-Butyramidophenol (58 g.; prepared according to Fierz-David and Kuster, loc.cit.), acetyl chloride (25.4 g.) and benzene (500 ml.) were heated together under reflux until a solution formed (12 hours). This solution was cooled and treated with water. The benzene layer was separated and the aqueous layer was again extracted with benzene.

The combined benzene extracts were dried and evaporated to dryness under reduced pressure to give pbutyramidophenyl acetate (38 g.) as an off-white solid, mp. 102-l03C. A mixture of p-butyramidophenyl acetate (38 g.), aluminium chloride (80 g.) and 1,l,2,2-tetrachloroethane (250 ml.) was heated at 140C. for 3 hours. The reaction mixture was cooled and treated with iced water. The tetrachloroethane layer was separated and the aqueous layer was extracted with chloroform. The combined organic layers were extracted with 2N aqueous sodium hydroxide and the alkaline solution was acidified to pH 5 with concentrated hydrochloric acid. The acidified solution was extracted with chloroform and the chloroform extract was dried and concentrated under reduced pressure to give 5′-butyramido-2-hydroxyacetophenone 15.6 g.), m.p. 114l17C. A solution of 5-butyramido-2′- hydroxyacetophenone (15.6 g.) in ethanol (100 ml.) was added to an ethanolic solution of sodium ethoxide which was prepared from sodium (1.62 g.) and ethanol (100 ml.). The resulting solution’was evaporated to dryness under reduced pressure and dimethylformamide (100 ml.) was added to the solid’residue. Ap-

proximately ml. of dimethylformamide was removed by distillation under reduced pressure. Epichlorohydrin ml.) was added and the solution was heated at 100C. for 4 hours. The solution was concentrated under reduced pressure to give a residual oil which was treated with water to’give a solid. The solid was dissolved in ethanol and the resulting solution was treated with charcoal, filtered and concentrated under reduced pressure to give crude 5-butyramido- 2-(2,3-epoxypropoxy)acetophenone (16 g.), m.p. 1101 16C.

The crude compound may be purified by recrystallisation from ethyl acetate, after, treatment with decolourizing charcoal, to give pure 5′-butyramido-2′-(2,3- epoxypropoxy)acetophenone, m.p. 136138C.

CLINICAL TRIALS………… JAPAN

September 4, 2014 3:48 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Clinical trials

Clinical trials, also known as clinical studies, are scientific studies of drugs, medical devices or other treatments in humans. These studies are most often conducted for the following reasons:

To verify the safety and effectiveness of potential drugs, medical devices or other treatments,
To compare trial-treatments against existing treatments,
To determine better ways to use treatments to make them more effective, easier to use, or to decrease side effects,
To determine how best to use a treatment in a specific population. For example, in children or in a particular ethnic group.

Clinical trials for new drug development

There are three main stages in clinical trials for drug development: Phases I, II and III. Phase I clinical trials are conducted with 50~200 healthy participants and involve incremental dose increases of investigational drug within a predefined dose range to evaluate tolerability and safety, monitor food and drug interaction, as well…

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The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

September 4, 2014 3:35 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

The following details the necessary procedure for the commencement of manufacture (or importing) of drugs in Mie Prefecture, Japan.
Note: The procedures described below are applicable in Mie Prefecture, Japan, as of April 2002. Due to future amendments and the disparities of laws in different prefectures, it is necessary to be informed as to the correct application procedures directly by the relevant prefecture.

1. For Manufacture (or Importing) of Drugs

Approval for the manufacture (importing) of each item, and a manufacturing (importing) license are required for the manufacture (or importing) of drugs.

Drug Manufacture	Approval	The quality, effectiveness and safety of the drug under application must pass the examination. However, drugs listed on the Pharmacopoeia of Japan do not require approval.
License	The structural conditions (building and facilities) and human resource requirements (e.g. Administrators) of the drug manufacturing facilities must pass…

View original post 2,249 more words

Bacteria responsible for gum disease facilitates development and progression of rheumatoid arthritis

September 4, 2014 3:08 am / Leave a comment

CLINICALNEWS.ORG

10 AUG 2012

Gum disease 4 times as common in rheumatoid arthritis patients
Might be potential trigger and/or help sustain inflammation suggest researchers

Gum disease is not only four times as common among patients with the autoimmune disease rheumatoid arthritis as it is among their healthy peers, but it also tends to be more severe, indicates a small study published online in the Annals of the Rheumatic Diseases.

The researchers base their findings on 91 adults with confirmed rheumatoid arthritis (RA) and a comparison group of 93 healthy people, matched for age and sex.

All participants were non-smokers, as smoking is a known risk factor for rheumatoid arthritis. And it is strongly associated with the production of antibodies, indicative of a systemic reaction to a person’s own proteins (ACPAs), and which often predates the development of rheumatoid arthritis by several years.

And none had been treated with arthritis drugs known…

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AMBROXOL

September 2, 2014 8:17 am / 1 Comment on AMBROXOL

Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body’s natural defence mechanisms. It stimulates synthesisand release of surfactant by type II pneumocytes. Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to thebronchial wall, in improving its transport and in providing protection against infection and irritating agents.^[1]^[2] Ambroxol is often administered as an active ingredient in cough syrup.

Ambroxol is indicated as “secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply”.^[3]

Ambroxolhydrochloridetablets in Japan

There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well aseffervescent tablets.

Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acutepharyngitis.^[4] Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of Ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s,^[5]^[6] but explained and confirmed in more recent work.

Ambroxol is a potent inhibitor of the neuronal Na+ channels.^[7] This property led to the development of alozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies^[4] have demonstrated the efficacy of Ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson’s disease.

Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. It is the active ingredient of Mucosolvan, Lasolvan or Mucoangin. The substance is a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract which play an important role in the body’s natural defence mechanisms. It stimulates synthesis and release of surfactant by type II pneumocytes. Surfactants acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.

Brief background information

Salt	ATC	Formula	MM	CAS
–	R02AD05 R05CB06 R07AA03	C ₁₃ H ₁₈ Br ₂ N ₂ O	378.11 g / mol	18683-91-5

Systematic (IUPAC) name

trans-4-(2-Amino-3,5-dibrombenzylamino)-cyclohexanol
Clinical data
AHFS/Drugs.com	International Drug Names

Identifiers

ATC code	R05 CB06
PubChem	CID 2132
ChemSpider	10276826
UNII	200168S0CL
KEGG	D07442
ChEMBL	CHEMBL153479
Chemical data
Formula	C₁₃H₁₈Br₂N₂O
Mol. mass	378.10

Synthesis pathway

Синтез a)

Synthesis

Ambroxol synthesis.^[9]

melting point

233-234.5

Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US. Patent 3,536,713; October 27, 1970; assigned to Boehringer lngelheim G.m.b.H.

Kack, J., Koss, F.W., Schraven, E. and Beisenherz, G.; US. Patent 3,536,713; October 27,
1970; assigned to Boehringer lngelheim G.m.b.H.

Trade Names

Page	Trade name	Manufacturer
Germany	Ambrobeta	betapharm
	AmbroGEKSAL	Hexal
	Mucosal	Boehringer Ingelheim
	various generic drugs
France	Muksol	Leurquin Milan
France	Surbronk	Boehringer Ingelheim
Italy	Ambrotus	Epifarma
	ATUS	Metapharma
	Mukoarikodil	Menarini
	Mucosal	Boehringer Ingelheim, 1982
	Viskomucil	Institute of Organic Chem.
Japan	Mucosal	Teijin
Ukraine	AMBROKSOL	Ltd. “Pilot Plant” HNTSLS “m. Kharkiv, Ukraine
	Ambroxol hydrochloride	CJC BHFZ, m. Kyiv, Ukraine
	AMBROBENE	ratiopharm GmbH, Germany
	LAZOLVAN®	Boehringer Ingelheim International GmbH, Germany
	various generic drugs

Formulations

ampoule 15 mg;
Capsules of 45 mg, 75 mg;
drops 7.5 mg, 30 mg,
dry syrup 1.5%, 3%;
Effervescent tablets 30 mg, 60 mg;
coated tablets 30 mg, 60 mg;
granules 1.5%, 3%;
inhalation solution of 7.5 mg;
inaektsiya 1.000 mg;
solution of 0.3%, 0.75%;
Syrup 0.3%;
Tablets of 15 mg, 30 mg, 60 mg (hydrochloride)

Chemical structure for Ambroxol

Ambroxol hydrochloride; Ambroxol HCl; 23828-92-4; Mucosolvan; Mucoangin; UNII-CC995ZMV90; SBB056993

Molecular Formula: C₁₃H₁₉Br₂ClN₂O Molecular Weight: 414.56376

2-Amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine
4-[(2-amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride(1:1)

References

Sanderson RJ et al. (1976), “Morphological and physical basis for lung surfactant action”, Respir Phys 27 (3): 379–92, doi:10.1016/0034-5687(76)90066-9,PMID 989610
Kido H et al. (Nov 2004), “Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential.”, Biol Chem 385 (11): 1029–34, doi:10.1515/bc.2004.133, PMID 15576322
Malerba M, Ragnoli B. (August 2008), “Ambroxol in the 21st century: pharmacological and clinical update”, Expert Opin Drug Metab Toxicol. 4 (8): 1119–29,doi:10.1517/17425255.4.8.1119, PMID 18680446
de Mey C. et al. (2008), “Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat”, Arzneimittelforschung 58 (11): 557–68,doi:10.1055/s-0031-1296557, PMID 19137906
Püschmann S, Engelhorn R. (1978), “Pharmakologische Untersuchungen des Bromhexin-Metaboliten Ambroxol (Pharmacological study on the bromhexine-metabolite ambroxol)”, Arzneimittelforschung 28 (5a): 889–98, PMID 581987
Klier KF, Papendick U. (1977), “Die lokalanaesthetische Wirkung von NA-872-haltigen Augentropfen (The local anesthetic effect of NA872-containing eyedrops)”, Med Monatsschr. 31 (12): 575–8, PMID 593223
Weiser T. (2006), “Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels”,Neurosci Lett. 395 (3): 179–84, doi:10.1016/j.neulet.2005.10.058, PMID 16293367
[1] Drugs.com, Ambroxol, accessed 21 January 2014
http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-ambroxol_30.html

DE 1 593 579 (Thomae; appl. 10.5.1966).
DOS 2 218 647 (Thomae; appl. 18.4.1972).
DOS 2 223 193 (Thomae; appl. 12.5.1972).
Keck, J.: Justus Liebigs Ann. Chem. (JLACBF) 707, 107 (1967).

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The Procedure for Manufacturing Drugs in Mie Prefecture, Japan.

1. For Manufacture (or Importing) of Drugs

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Synthesis

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