5 Registration and toxicological data

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5.1 Registration 5.1.1

Pharmaceutical products 5.1.1.1

General

An auxiliary such as povidone, crospovidone or copovidone cannot be registered as such by the authorities for use in pharmaceutical products. In Europe, Japan or America, it is always only possible to register a finished drug. There is no general positive or negative list of auxiliaries used in pharmaceuticals. It is only possible to state in which countries pharmaceuticals that contain povidone, copovidone and/or crospovidone are registered.

5.1.1.2 Pharmacopoeias

In practice, a pharmaceutical preparation that contains povidone, copovidone and/or crospovidone can only be registered if these auxiliaries meet the require- ments of the monographs in the pharmacopoeias that are regarded as mandatory in the countries concerned. The products described in this book meet these requirements (Table 183).

The monograph “Povidone” is in stage 5 to be worldwide harmonized.

Table 183. Excipients of this book covered by pharmacopoeias

Product Ph.Eur. USP-NF J.P./J.P.E.

Povidone K 12 + + n. a.

Povidone K 17 + + +

Povidone K 25-90 + + +

Crospovidone + + +

Copovidone + + +

n.a. = Monograph not available

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222 5 Registration and toxicological data

5.1.1.3 Registrations in individual countries

Pharmaceutical products that contain povidone, crospovidone or copovidone have been registered in all important drug markets like Europa, USA, Japan etc.

for parenteral, oral and topical administration.

The following limitations apply to povidone in injectables:

1. Japan

Up to 2001 Povidone K 12 was only registered in one human injectable, and povidone K 17 in different human preparations.

2. Europe

The use of povidone in finished parenteral preparations was regulated in Ger- many by the Federal Health Ministry in 1983 [214]:

– The K-value must be smaller than 18.

– The packaging and the package insert of the finished declaration must declare the quantity used.

– Attention must be drawn to the possibility of accumulation in the organism after frequent administration.

– For intramuscular administration a maximum of 50 mg of povidone is per- mitted per individual dose.

Similar regulations also apply in other european countries.

5.1.1.4 Drug Master File (DMF)

Drug Masters Files are only required for the registration of excipients not includ- ed in the Pharmacopoeias as monographs. Therefore for povidone, crospovidone and copovidone a DMF is not needed for the registration of a drug containing one of these excipients.

5.1.2 Food 5.1.2.1 General

While there are no such lists for pharmaceutical products, various countries have

positive lists regulating the use of auxiliaries in food. These lists include soluble

and insoluble polyvinylpyrrolidone, though in some cases only for certain appli-

cations.

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5.1.2.2 ADI value

In 1987 the World Health Organization (WHO + FAO) specified an Accepted Dai- ly Intake (ADI) value for soluble polyvinylpyrrolidone (povidone) in food of 0–50 mg/kg body weight [372]. For Crospovidone the ADI value is “not specified” and therefore no limit is given for the application in foods [215].

5.1.2.3 Registration of povidone in the Europe and USA

In the European Union soluble polyvinylpyrrolidone having a nominal K-value of 25, 30, or 90 has got the E-number E 1201 for the use in dietary food supplements in (coated) tablet form and in sweetener preparations.

Povidone with an average molecular weight of 40 000 (povidone K 30) is regis- tered for use in the USA in the manufacture of the foods listed in Table 184, sub- ject to certain restrictions [487].

In the USA, povidone with a number average molecular weight of 360 000 (povidone K 90) is permitted for use as a clarifying agent for beer. The amount remaining in the beer must not exceed 10 ppm.

5.1.2.4 Registration status of crospovidone for use in food in different countries

In the European Union insoluble polyvinylpyrrolidone (“polyvinylpolypyrroli- done”) has got the E-number E 1202 for the use in dietary food supplements in (coated) tablet form and in sweetener preparations.

Table 184. Registration of povidone K 30 for use in food in the USA

Food Purpose Conditions of use

Wine Clarifying agent Residue <60 ppm

Vinegar Clarifying agent Residue <40 ppm

Vitamin, mineral or flavouring Tabletting auxiliary According to cGMP

concentrates in tablet form rules

Sweetener tablets Tabletting auxiliary According to cGMP rules

Vitamin and mineral Stabilizer, According to cGMP

or sweetener concentrates in dispersant, rules

liquid form thickener

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224 5 Registration and toxicological data

Crospovidone is usually registered as “polyvinylpolypyrrolidone” or “PVPP” – in the USA for clarifying beverages and vinegar [488] and in all european and many other countries for stabilizing and clarifying beer and wine.

5.2 Toxicological data 5.2.1

Povidone and crospovidone

There are a large number of publications on the good tolerance of polyvinyl- pyrrolidone [127–129, 131, 133–134, 201, 225]. A complete list with assessments is to be found in “A Critical Review of the Kinetics and Toxicology of Polyvinylpyrroli- done” by Robinson, Sullivan, Borzelleca and Schwartz, published in 1990 [225].

Because of the good tolerance of povidone, its Accepted Daily Intake (ADI) was adjusted to 0–50 mg/kg body weight by the FAO/WHO Joint Expert Committee for Food Additives (JECFA) in 1987 [372].

In 1983, the JECFA awarded crospovidone an ADI status of “not specified”, as on the basis of the available chemical, biochemical, toxicological and other data, the entire daily intake of the substance in the quantities to be expected did not represent any risk to health in the opinion of the JECFA. It therefore seemed unnecessary to set a numerical value for the ADI [215].

Many toxicological and biochemical studies have been carried out with the individual grades of povidone and crospovidone by the producers. They could be ordered there.

There is also a published study on renal elimination after intravenous admin- istration of povidone K 12 and K 17 in rats [97].

The following summary of toxicological properties is taken from the book

“A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone” [225]:

Toxicology and Safety

An extensive body of toxicological data in animals supports the biological inert-

ness of PVP. The acute, subchronic, and chronic toxicity of orally administered

PVP is extremely low, with the only effect observed being diarrhea at high doses

due to the osmotic action of PVP acting as a bulk purgative. Occasional observa-

tions of minimal absorption with storage in mesenteric lymph nodes seem to be

of no toxicological importance. PVP is neither a sensitizer nor an irritant. There

are no reported adverse effects following oral administration in humans. The cur-

rently permitted FAO/WHO ADI of 0 – 50 mg/kg body weight for food uses pro-

vides an adequate margin of safety. There would appear to be no reason to restrict

its oral or topical pharmaceutical use or topical cosmetic use in any way. There

have been no reports of adverse effects following its use intravenously as a plasma

expander, even after the administration of very large amounts. The only toxico-

logical problems have involved the repeated injection of large amounts of the

higher molecular weight material into poorly perfused sites such as subcuta-

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neously and into the breast. If the use of PVP in injectables for repeated use is restricted to PVP with a molecular weight less than K-18 in limited amounts (e. g.

50 mg/i. m. dose) and the injection sites are varied, and intramuscular or intra- venous routes are used, then these problems should not occur. The repeated use of PVP in depot preparations, which could lead to excessive storage, is not to be recommended.

5.2.2 Copovidone

Copovidone has no acute toxicity and does not irritate the skin or mucous mem- branes. Prolonged administration to rats and dogs was tolerated without recog- nizable undesirable side effects.