Pharma & Healthcare News July 2011

Pharma & Healthcare News Alsiano No. 14 • July 2011

Contents New micro-encapsulated solubiliser for direct compression . ..........................1 Meeting the challenge of age and cellular oxidation ................................3 EXTRAMEL reduces stress and improves vitality .............4 High purity inorganic salts for pharma & biotech from Jost Chemical . ...............5 New study proves rooibos’ antioxidant potency . .............6 Amla - a new addition to the superfruit range ..........7 The Alsiano Healthcare team ........................................8

New micro-encapsulated solubiliser for direct compression SEPITRAPTM is a patented innovation designed for solid oral dosage forms. This micro-encapsulated solubilising agent improves the bioavailability of pharmaceutical active ingredients

By Seppic Oral route is the easiest way to administer a drug. In order to cross the intestinal wall to be absorbed, the drug must dissolve into the organism fluids. That is why the solubility and dissolution of drugs are of extreme importance.

On the other hand, a molecule must often possess a lipophilic group to have affinity towards the cellular target receptor and, as a consequence, most of the new chemical compounds discovered by high throughput screening have poor water solubility.

More than 40% of new chemicals are rejected because of that fact, and still more than 70% of drugs of synthetic nature have solubility issues.

Publisher: Alsiano A/S Circulation: 650 copies Editor-in-chief: Anders Hager Coordinator, text, lay-out: Dorthe Andersson Pharma & Healthcare News is published twice a year and distributed to customers and other interested parties. Reproduction of articles appearing in Pharma & Healthcare News requires prior consent of the author. Alsiano is not responsible for the content of articles written by external authors.

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Improving bioavailability The most widely used solution for improving bioavailability of a molecule is the use of surfactants.

Surfactants are amphiphilic molecules that are able to form micelles with a lipophilic core and a hydrophilic shell creating a tank for the poorly soluble molecules, enabling their absorption.

However, the solubilisers are commonly present as liquids compelling the formulator to use the long and energy-costly wet granulation process making tablets or hard capsules.

To solve this problem encountered by every pharmaceutical company SEPPIC has an innovative solution: SEPITRAPTM. continues on page 2 >>

Pharma & Healthcare News Food News

• July 2011

No. 1No.• 14 February 2004

>> The SEPITRAPTM range SEPITRAPTM is a patented technology consisting of dry surfactants that can be directly incorporated into oral solid drug forms through direct compression. At present, the SEPITRAPTM range contains SEPITRAPTM 80 and SEPITRAPTM 4000, both composed of a non-ionic hydrophilic surfactant encapsulated into a mineral carrier. All components of both variants comply with their monograph in European Pharmacopeia and USP/NF when available.

How does it work?

In SEPITRAPTM, the surfactant is microencapsulated in the mineral carrier thus presenting as a free flowing powder.

The hydrophilic surfactants used have a higher affinity to water than the carrier. As a consequence, when SEPITRAPTM is dispersed into the organism fluids, more than 80% of the microencapsulated solubiliser desorbs from the carrier in 5 minutes and is available to solubilise the active.

Alsiano Alsiano

Dissolution improvement Ratio drug: SEPITRAPTM Medium

API

Solubility µg/mL

SEPITRAPTM 4000

SEPITRAPTM 80

Cyclosporin A

2:1

water

9.53

x 2.9

x 2.4

Telmisartan

2:1

water

3.51

x 3.6

x 3.6

Itraconazole

2:1

water

9.64

x 81

x 7.5

Carbamazepine

8:1

0.1N HCI

17.7

x 1.5

-

Table 1: dissolution improvement of various APIs with both SEPITRAPTM

2 hours for the surfactant to solubilise the API when the wet granulation process is used vs 30 minutes for SEPITRAPTM. Moreover, the micro-encapsulation does not affect the solubilising power of the surfactant.

Studies in Korea and France have shown similar results for other APIs such as cyclosporine A, telmisartan, itraconazole and carbamazepine. The API solubilised can be increased from 1.5 to 81 times when using SEPITRAPTM vs the raw API.

Case study: Fenofibrate Fenofibrate is a lipopenic API very poorly soluble in water: less than 0.1 mg/L. Using the pharmacopoeia dissolution test, no more than 0.005% of the fenofibrate incorporated in a 200 mg-containing tablet is dissolved. When SEPITRAPTM 4000 is added, the dissolution increases up to 1% - i.e. 200 times more!

Technical data Both SEPITRAPTM variants offer a flowability at less than 10 s at up to 20% of SEPITRAPTM in the formula.

These results are also seen with the same surfactant using a wet granulation process but with a delay: it takes

SEPITRAPTM slightly decreases the hardness of tablets but it remains within an acceptable range. The ad-

Which SEPITRAPTM is going to be the best solubiliser is not predictable, but it is very easy to find out by experimenting.

vised maximum amount is around 20%, but good results can already be reached at 5% of excipient.

Formulation trials have also been done for the making of hardgel capsules showing very good results.

Article 363

“SEPITRAPTM is developed to improve solubilisation and simplify customer’s process at the same time”

Drug release [%]

1.2%

Branded Fenofibrate 200 mg + SEPITRAPTM 4000 300 mg

0.8%

Introduction of SEPITRAPTM 4000 0.4%

0.005% 0 min

Branded Fenofibrate 200 mg

10 min

20 min

30 min

40 min

50 min

Time [min]

Graph 1: drug release in the medium raw API vs. SEPITRAPTM

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SEPITRAPTM: Microencapsulated Solubiliser

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July 2011

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Meeting the challenge of age and cellular oxidation Lynside YE Glutathione, developed by Lesaffre, is a yeast extract rich in reduced glutathione and in its precursors, γ-Glu-Cys. Lynside YE Glutathione contains the essential amino acids to maintain optimum glutathione level in humans

By Lesaffre Human Care

Our body constantly reacts with oxygen as we breathe and our cells produce energy. As a consequence of this activity, highly reactive molecules – free radicals – are produced and can cause oxidative damage implicated in many diseases and have an impact on the body’s ageing process.

There are lots of antioxidants in our foods and supplements, but we often forget the principal antioxidant, a tiny molecule hidden in human cells, called glutathione. Glutathione is essential to the fight against free radicals and we have to constantly replenish this antioxidant to achieve optimum health. Despite the documented importance of glutathione, there is no recommended daily intake for this tripeptide.

Glutathione – a major antioxidant Glutathione, also called γ-L-GlutamylL-cysteinyl-glycine, or GSH, is a molecule synthesised in the the human body from glutamic acid, cysteine and glycine. Present in quite large quantities in cells, this tripeptide enables

many biological functions, thanks to the reactivitity of its thiol (-SH) function. This makes GSH a powerful antioxidant that participates in the body’s cellular defence mechanisms.

A well-balanced intake of amino acids enables adults to synthesise enough GSH to ensure proper functioning of their bodies, but with ageing and certain age-related diseases such as Alzheimers’1 or Parkinson’s2, GSH levels diminish. Certain studies even suggest that drops in glutathione levels due to ageing could be the source of a certain number of changes that occur at the onset of various diseases3. Dietary supplementation may then be necessary. For GSH levels to be maintained, three types of intake are possible: • intake of GSH • intake of amino acids, precursors of GSH • intake of vitamins B6, B9 and B12, which regulate the levels of homocysteine in the blood (and thereby regulate the levels of neoformed cysteine).

Lynside YE Glutathione Lynside YE Glutathione is a yeast extract rich in glutathione. Since saccharomyces cerevisiae yeast is grown on a medium favouring endogenous synthesis of glutathione, Lynside YE Glutathione is rich in both glutathione and glutathione precursors.

The advantages of using Lynside YE Glutathione are the following: • GSH can be utilised directly in the intestinal lumen where it has a detoxification role4.

• Since specific transport systems with di- and tripeptides have been identified5, we can presume that after consuming Lynside YE Gluta-

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Lynside YE Glutathione Indicative values for a batch: GSH > 5% γ-Glu-Cys > 1% Glutathione equivalent* > 8% *concentrations of Cys and Glu-Cys precursors are taken into account.

• thione, a certain quantity of GSH goes directly into the blood circulation. This was suggested by Hagen et al.6,7 when they showed that dietary GSH can be absorbed intact into the small intestine and, hence, a substantial increase in blood plasma GSH was observed.

• The glutathione of Lynside YE Glutathione can also be broken down to supply the amino acids that are precursors of intracellular GSH biosynthesis.

• Finally, Lynside YE Glutathione contains γ-Glu-Cys (an intermediary of glutathione synthesis), cysteine and glycine, which are precursors of intracellular GSH biosynthesis.

Article 364 References:

1. Liu H. et al, 2004, Glutathione metabolism during ageing and in Alzheimer disease, Annals of the New York Academy of Sciences; 1019:346-9.

2. Sian J. et al, 1994, Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia, Annals of neurology; 36(3):348-55.

3. Schulz J.B. et al, 2000, Glutathione, oxidative stress and neurodegeneration, European Journal of biochemistry; 267(16):4904-11. Review.

4. HE M. et al, 2004, Total Equivalent of Reactive Chemicals in 142 Human Food Items is Highly Variable Within and Between Major Food Groups, The Journal of nutrition; 134(5):1114-9.

5. Zaloga GP. et al, 1991, Effect of enteral diets on whole body and gut growth in unstressed rats, Journal of parenteral and enteral nutrition; 15(1):42-7.

6. Hagen TM. et al, 1990, Bioavailability of dietary glutathione: effects on plasma concentration, The American journal of physiology; 259 (4 Pt 1): G524-9.

7. Hagen TM. et al, 1987, Transepithelial transport of glutathione in vasculary perfused small intestine of rat, The American journal of physiology; 252(5 Pt 1): G607-13.

Pharma & Healthcare News

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July 2011

Alsiano

EXTRAMEL reduces stress and improves vitality New clinical study confirms that EXTRAMEL melon juice concentrate rich in SOD reduces perceived stress and physical and cognitive fatigue in healthy people and is recognised to be a powerful enzymatic antioxidant able to fight against oxidative stress.

Anti-stress and anti-fatigue effect of EXTRAMEL confirmed A first clinical study by Milesi et al, published in Nutrition Journal in 2009, demonstrated the reduction of stress induced by a one-month supplementation with EXTRAMEL5.

These results are now confirmed by a second clinical study.

By Seppic In developed countries, around 30% of the population is affected by stress and fatigue which are closely linked and often caused by a professional activity1. An imbalance between physical and psychical fatigue and the recovery thereof can ultimately lead to a stage known as the “burn out” syndrome.

Recent studies have demonstrated a correlation between psychological stress (at the subject level) and oxidative stress (at the cell level)2,3,4. In this context, it seems interesting to consider a nutritional ingredient that contributes to the maintenance of this fragile balance: SOD (superoxide dismutase) is the main antioxidant enzyme in living cells and organisms,

This double blind placebo controlled study has once again shown that EXTRAMEL is able to significantly reduce stress in healthy people (see figure 1) and improve their quality of life (see figure 2). In addition, it was observed that after 84 days of supplementation, the level of perceived stress still remained lower than before supplementation. According to the study, EXTRAMEL supplementation showed also very beneficial for the complete fatigue condition, by reducing both physical and cognitive fatigue.

Material and method The second clinical study was a multicentric, double-blind, placebo controlled study taking place in two different ... continues on page 5 >>

Figure 1: Perceived stress - Cohen PSS-14 scale

EXTRAMEL bioactive SOD The EXTRAMEL range was developed by BIONOV following the discovery of a melon variety that aged slowly due to its high SOD (superoxide dismutase) content.

SOD is an antioxidant enzyme that is naturally present in cells of living beings. It is a cell’s first line of defence against reactive oxygen species (free radicals). Due to its enzymatic nature, it has an extremely powerful antioxidant activity.

Products of the EXTRAMEL range have been developed in order to provide benefits of the SOD that is naturally present in this exclusive melon variety. The development of several encapsulation technologies has made it possible to make this SOD bioactive in oral application.

EXTRAMEL exists in several grades and may be used for the manufacture of: • drinks • dietary products • dairy products • dietary supplements

Figure 2: Quality of life - SF-36 scale Placebo

Placebo

D28

D84

D0

A placebo effect exists between D0 and D28; however, it stops after 28 days of supplementation. EXTRAMEL supplementation significantly reduced perceived stress after 28 days and after 84 days. This anti-stress effect is maximised after 28 days (-11.4%) and is significantly higher than the placebo effect. **p < 0.01

D28

Better quality of life

D0

EXTRAMEL

Higher perceived stress

EXTRAMEL

D84

A placebo effect exist between D0 and D28; however, it stops after 28 days of supplementation. EXTRAMEL supplementation significantly improved quality of life (= lower score at SF-36 scale) after 28 days and after 84 days (20%), and significant relative to placebo group. **p < 0.01

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Pharma & Healthcare News

No. 14

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July 2011

Alsiano

High purity inorganic salts for pharma & biotech from Jost Chemical Full traceability, experienced technical support and in-house manufacturing and testing of all products make Jost Chemical a preferred partner

By Jost Chemical Jost Chemical manufactures a broad range of inorganic salts used as biological buffers and process intermediates by the pharmaceutical, biotech and diagnostic industries. Inorganic salts are used in API synthesis, vaccine manufacturing, fermentation processes and cell culture media.

Stringent quality requirements ensure that Jost provides customers with high purity, lot to lot consistent products that meet your specifications every time. Jost operates under ICH Q7 bulk pharmaceutical cGMPs and is audited regularly by the FDA and customers in the pharmaceutical and biotech industries.

High purity inorganic salts from Jost are manufactured to meet USP/EP/BP/

JP/ACS and multi-compendial requirements. All products are manufactured and fully tested in house and are BSE/TSE free.

Traceability Jost Chemical's adherence to GMP manufacturing assures all finished goods are fully traceable "backwards" to the raw materials and "forwards" into the final packaging and ship-to location for every container comprising the production lot.

Technical support Jost's experienced and dedicated technical staff responds quickly and thoroughly to customer requests for product solutions, information, and specific test requirements. Low levels of vagrant metals are reported using ICP-MS. Article 365

Examples of inorganic salts for pharma and biotech applications • Ammonium Phosphate Monobasic ACS • Ammonium Phosphate Dibasic NF/ ACS • Ammonium Sulfate NF/ACS • Cupric Sulfate Pentahydrate USP • Ferrous Ammonium Sulfate Purified • Manganese Sulfate Monohydrate USP/EP/ACS • Potassium Carbonate ACS • Potassium Phosphate Monobasic NF/EP/BP/ACS • Potassium Phosphate Dibasic USP/ ACS • Potassium Sulfate EP/ACS • Sodium Caprylate NF/EP • Sodium Carbonate Anhydrous NF/ EP/JP/ACS • Sodium Carbonate Monohydrate NF/ACS • Sodium Phosphate Monobasic Monohydrate USP/BP/ACS • Sodium Phosphate Dibasic Anhydrous USP/EP/ACS • Sodium Phosphate Dibasic Heptahydrate USP/ACS • Sodium Phosphate Tribasic Dodecahydrate ACS • Sodium Sulfate Anhydrous USP/ACS

>> investigation centres in France between November 2008 and April 2010. The population of the study consisted of 61 healthy subjects 30 to 65 years old with a certain level of stress and fatigue but without any depressive symptoms.

The treatment consisted of 84 days of supplementation with small hard capsules containing 10 mg EXTRAMEL microgranules (each containing 140 IU of SOD) and starch only for the placebo group. Evaluation was per-

formed during a medical visit at the beginning (D01), after 28 days (D28) and at the end of the supplementation period (D84).

For more information about the study, please contact Alsiano.

References 1. Nasse P, Légeron : Rapport sur la détermination, la mesure et le suivi des risques psycosociaux au travail.

France, Ministère du travail, des relations sociales et de la solidarité, Rapport public, Mars 2008 2. Grossi G, Perski A, Evengard B, Blomkvist V, OrthGomer K : Physiological correlates of burnout among women. J Psycho Res 2003, 55:309-316

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3. Casado A, De Lucas N, Lopez-Fernandez E, Sanchez A, Jimenez JA: Lipid peroxidation, occupational stress and ageing in workers of a prehospital emergency service. Eur J Emerg Med 2006, 13(3):165-17.

4. Hovatta I, Tennant RS, Helton R, Marr RA, Singer O, Redwine JM, Ellison JA, Schadt EE, Verma IM, Lockhart DJ, Barlow C: Glyoxalase 1 and gluthathione reductase 1 regulate anxiety in mice. Nature 2005, 438(7068):662-666.

5. Milesi MA, Lacan D, Brosse H, Desor D, Notin C: Effect of an oral supplementation with a proprietary melon juice concentrate (EXTRAMEL) on stress and fatigue in healthy people: a pilot, double-blind, placebo-controlled clinical trial. Nutr J 2009, 8: 40

Article 366

Pharma & Healthcare News

No. 14

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July 2011

Alsiano

New study proves rooibos’ antioxidant potency A collaborative study by scientists at four international research facilities has found the first clinical evidence that drinking rooibos tea significantly increases the antioxidant capacity in human blood, thereby boosting the body’s natural defences By the South African Rooibos Council The researchers in Rome and Glasgow found that the antioxidant capacity in the blood of 15 healthy volunteers peaked one hour after drinking 500 ml ready-to-drink rooibos tea. Both traditional (fermented) and green (unfermented) rooibos tea had a significant effect.

“On the basis of the results of our study, we conclude that rooibos tea is able to deliver antioxidant ingredients to the body, thereby stimulating the body’s internal redox network”, says Professor Mauro Serafini, leader of this research project and Head of the Antioxidant Research Laboratory at INRAN, a nutrition research institute in Rome, Italy. “It is highly possible that, once absorbed in the circular stream, the unique ingredients of rooibos may display other biological activities in the human body.

That is why we are planning further intervention studies in humans to investigate the effect of rooibos tea on the body’s strategy of defence to counteract the development of heart disease.”

“After an hour, the plasma antioxidant levels start to drop and that is why we recommend drinking up to six cups of rooibos spaced throughout the day for a sustained health benefit”, explains Professor Jeanine Marnewick from the Cape Peninsula University of Technology. She led a recent study that showed the beneficial effect of drinking six cups of rooibos a day to promote heart health.

Numerous studies over the past few decades have helped scientists to understand the complex and unique blend of antioxidants found in rooibos. They have also proved that the active compounds in rooibos are bio-

available and are metabolised (converted) in the body. The significance of the latest study is that it provides the first direct evidence that rooibos boosts antioxidant levels in the blood of healthy humans.

“This new reseach proves that the compounds in rooibos are potent enough to have a measurable effect on the antioxidant capacity of the blood”, says Professor Lizette Joubert, one of South Africa’s leading rooibos researchers, working on the quality and chemical composition of rooibos at South Africa’s Agricultural Research Council.

The most active antioxidant in rooibos – aspalathin – is unique to the plant species Aspalathus linearis. This fynbos plant thrives in the Western Cape’s Cedarberg region where it is commercially cultivated and wild-harvested for the production of rooibos tea.

“This study underlines the value of rooibos as a widely available and affordable source of dietary antioxidants”, comments Mientjie Mouton, chair of the Product Research Committee of the South African Rooibos Council. “It is very encouraging that leading research institutions around the world are working on rooibos and producing such promising results. There is also a great deal of work being done by local rooibos researchers and we will continue to invest in this research”.

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The South African Rooibos Council invests some R1 million (approx.

100.000 EUR) a year to fund research into rooibos’ health properties. Last year, the Council supported research projects at several local universities and science councils focusing on how rooibos can counter cancer and stress, as well as the link between rooibos and exercise. A project on rooibos and obesity has been approved for funding in 2011.

Summaries of the most recent rooibos studies published in top peerreviewed scientific journals can be found on the website of the SA Rooibos Council at www.sarooibos.co.za.

Article 367

Pharma & Healthcare News

No. 14

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July 2011

Alsiano

Amla – a new addition to the superfruit range Amla is a new antioxidant superfruit promoting health and antiageing. This highly nutritious fruit is an important dietary source of vitamin C, polyphenols, minerals and amino acids

By Annette Strarup, Area Sales Manager, Alsiano

ALSIANO SUPERFRUIT RANGE Acerola Acai Amla Berry Baobab Bilberry Black Currant Cranberry Goji berry Hawthorn Pomegranate

Amla (Emblica officinalis), also known as Indian gooseberry, grows particularly in South India, Ceylon and Malaya. It has a place in Ayurveda as a nurturing food proving a number of health benefits and used to support wellness and healthy ageing. The fruit is thus used as a major constituent in several Ayurvedic preparations – e.g. Chyawanprash tonic used to support strength and immune system and the composition Triphala to support digestive health. Amla fruit holds a strong reputation in Asia as an antiageing superfruit and is also called the “beauty fruit”.

Rich in vitamin C Amla is rich in Vitamin C. In addition to this, several active tannoid principles have been identified which appear to account for its health benefits. Amla contains the following tannins and polyphenols: • Emblicanin A and B • Ellagic acid • Puniglucanin • Pedunculagin • 2-keto-gluconolactone (vitamin C equivalents) • Hexahydroxy-diphenic acid and conjugates

The fruit also contains a high concentration of amino acids and many minerals such as Zn, Cu and Cr attenuating oxidative stress. Glutamic acid, proline, aspartic acid, alanine and lysine are 29.6%, 14.6%, 8.1%, 5.4% and 5.3% respectively of the total amino acids.

Natural Medicine Comprehesive Database states that Amla extract demonstrates antioxidant, antiinflammatoric, immuneboosting and antimicrobial properties.

Beauty supplements and functional beverages In modern supplements, Amla is used in beauty supplements to boost skin care from within. Amla also helps to strengthen the liver and helps to purify and clean the blood, which will enhance texture and shine of the skin.

Furthermore, Amla is recommended for use as antioxidant in beauty supplements together with “skin building blocks” such as collagen, hyaluronic acids or ceramides. Collagen and ceramides are available from Alsiano.

Amla also has a tradition in India for being used to improve eyesight, but

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no modern studies exist on this indication.

For beverages, Amla is not yet accepted by mainstream consumers like other superfruits such as pomegranate, but some product launches are already seen in Europe. Amla may therefore turn out to be the next superfruit star in juices, yoghurts and smoothies. continues on page 8 >>

Pharma & Healthcare News

No. 14

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July 2011

Alsiano

The Alsiano Healthcare team It is always nice to be able to put a face on the person you talk to over the telephone or e-mail. So here we are ...

Pharmaceuticals - cosmetics health & nutrition

Pharmaceuticals - cosmetics health & nutrition

Key accounts Anders Hager

Lene Aarøe Nissen

Annette Strarup

M.Sc. Chem.

Sales manager

B. Chem. Eng. Area sales manager

B.Sc. (Hons.) Chem. Eng. Area sales manager

E-mail: ahg@alsiano.com Tel. dir.: +45 8230 0026 Mobile: +45 2618 8545

E-mail: lan@alsiano.com Tel. dir.: +45 8230 0025 Mobile: +45 2270 1002

E-mail: ask@alsiano.com Tel. dir.: +45 8230 0049 Mobile: +45 2270 1015

Pharmaceuticals - Fermentation

Pharmaceuticals - cosmetics health & nutrition

Sales support

Annette Jarlskov

Henrik A. Petersen

Birgitte Falkensteen

M.Sc. Food Science Area sales manager

M.Sc. Pharm.

Senior area sales manager

Sales assistant

E-mail: aja@alsiano.com Tel. dir.: +45 8230 0072 Mobile: +45 2270 1017

E-mail: hap@alsiano.com Tel. dir.: +45 8230 0009 Mobile: +45 2067 1231

E-mail: bf@alsiano.com Tel. dir.: +45 8230 0006

Sales support

Sales support

Logistics

Malene Rask Harder

Signe Mørck

Lene Baldasano del Valle

Sales assistant

Sales assistant

Logistics manager

E-mail: mrh@alsiano.com Tel. dir.: +45 8230 0007

E-mail: sm@alsiano.com Tel. dir.: +45 8230 0042

E-mail: lb@alsiano.com Tel. dir.: +45 8230 0015

>> Vitamin C: amla and other sources Amla is an important source of vitamin C. The amla extract from Vidya Herbs is made from fresh amla fruit and not from dried fruits, making it possible to maintain a vitamin C content in the extract of 5%.

Vitamin C content in fruit pulp Acerola

Among other fruit extracts that contain vitamin C is Acerola, Rosehip and Baobab - also available from Alsiano. The respective vitamin C content of fresh fruit pulp and % in extract are shown in the table.

Amla Rosehip

Article 368

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Vitamin C content in extract from Alsiano

7200 mg/100 g

15%, 30%

720 mg/100 g

5%

1500 mg/100 g

15%, 30%