GB2031942A

GB2031942A - Medicated shampoo compositions

Info

Publication number: GB2031942A
Application number: GB7934034A
Authority: GB
Original assignee: Albright and Wilson Ltd
Current assignee: Solvay Solutions UK Ltd
Priority date: 1978-09-29
Filing date: 1979-10-01
Publication date: 1980-04-30

Abstract

A clear aqueous shampoo composition comprises a Zn, Mg, Mn, Ca or Fe salt of pyridine-2-thiol-1-oxide solubilised in aqueous media in the presence of a polynitrogen based surfactant. Surfactants produced by the carboalkylation of imidazolines having the formula:- <IMAGE> wherein R is C8-C20 alkyl or alkenyl, b is 1 to 8 and X represents hydrogen, hydroxy or carboxylate, may be used. The solubilisation is preferably carried out in the presence of greater quantities of surface active materials than that required to solubilise the salt of pyridine-2-thiol-1-oxide and most preferably such an excess is provided by a surfactant other than a polynitrogen based surfactant. The solubilised salts of pyridine-2-thiol-1-oxide exhibit enhanced antidandruff performance as compared with known shampoos.

Description

SPECIFICATION Shampoo compositions The invention relates to novel medicated shampoo compositions which are valuable in the treatment of dandruff and other related conditions of the scalp.

Such compositions comprise an active ingredient in combination with other cleansing agents such as surfactants.

One particular class of active ingredients which have been widely used are the salts of pyridine-2thiol-1-oxide. Shampoo compositions which comprise salts of this type are described in British Patent 957458. Essentially they comprise an aqueous system containing the salt of pyridine-2-thiol-1-oxide and a soap or a synthetic surfactant. At the neutral pHs required the pyridine-2-thiol-1-oxide salt is present as a suspension of solid particles which gives the composition a cloudy appearance which detracts from its appeal to the customer. Only the alkali metal salts of pyridine-2-thiol-1-oxide have been successfully incorporated into a neutral clear aqueous system but the use of these salts in shampoo compositions has been limited bytheirtoxic nature.The heavy metal salts of pyridine-2-thiol-1-oxide especiallythe zinc salt are preferred for use in shampoo formulations and the art has continued to attempt to formulate neutral clear aqueous shampoo compositions containing these salts. Gerstein (Journal of the Society of Cosmetic Chemists Volume 23 pages 99-114) has shown that the zinc salt can be dissolved in a variety of alkyl amines but when such solutions are formulated into a shampoo composition the presence of the required quantities of amine raises the pH of the shampoo to an unacceptably high level. If this pH is reduced by the addition of an acid pyridine-2-thiol-oxide or its salt is precipitated.

We have now discovered that the "heavy metal" salts of pyridine-2-thiol-l -oxide can be solubilised in aqueous media in the presence of certain nitrogen containing surfactants.

Useful surfactants include those polynitrogen based compounds having formula I or II below:

wherein R represents a saturated or unsaturated alkyl or alkenyl group comprising from 8-20 carbon atoms, A represents a hydrogen atom, a substituted or unsubstituted alkyl or alkenyl group comprising from 1 to 6 carbon atoms or a group of the formula R3COO- wherein R3 represents a substituted or unsubstituted alkylene group having from 1-4 carbon atoms, B represents an alkyl group comprising from 1-4 carbon atoms and X represents a hydrogen atom, a hydroxy group or where A does not represent a group of the formula R3COO- X may represent a carboxylate group, the suffixes a and care integers which may be the same or different having the value of from 1 to 3, b is an integer having a value of from 1 to 8, and Y represents a carboxylate group -COO- or a sulphonate group SO,. Other useful surfactants are those obtained by the reaction of carboalkylating agent of the formula Z R3COO- wherein Z represents a halogen atom and R3 is as herein before defined, with imidazolines of the formula Ill.

wherein R, R3, X and b are as hereinbefore defined.

The solubilisation may be achieved by mixing the pyridine-2-thiol-1-oxide salt with a surfactant or mixture of surfactants having the above formulae or obtained by the aforesaid reaction (hereinafter for convenience termed polynitrogen based surfactants) in an aqueous medium. The salt of pyridine-2thiol-1-oxide may be added as a granular solid or as a dispersion thereof in an aqueous medium.

The polynitrogen based surfactant and the pyridine-2-thiol-1-oxide salt are mixed together at temperatures above the ambient e.g. 50 to 950C pre ferably 65 to 85C with thorough mixing. The pyridine-2-thiol-1-oxide salt is preferably added in stages to an aqueous solution of the polynitrogen based surfactant. The formation of a clear product is indicative of solubilisation having taken place. Some solubilisation may be achieved when the mixing is carried out at room temperature but this is normally insufficientto obtain a product which can be incor porated into an aqueous shampoo composition comprising useful quantities of the active pyridine2-thiol-1-oxide salt.

The product of the solubilisation process is not necessarily a true solution. By solubilisation we mean a process which results in the formation of a liquid, which appears clear to the eye.

The process of solubilisation is made easier by the presence of other surfactant material. The formation of a clear liquid system which comprises a salt of pyridine-2-thiol-1 -oxide suitable for use in or as a shampoo composition can be achieved by: I) mixing the salt of pyrid i ne-2-th iol-l -oxide with a polynitrogen based surfactant or surfactants as hereinbefore defined.

II) mixing the salt of pyridine-2-thiol-1 -oxide with a polynitrogen based surfactant or surfactants in the presence of other surfactant material or Ill) mixing the salt of pyridine-2-thiol-1 -oxide with a shampoo composition which comprises a polynitrogen based surfactant or surfactants together with other conventional shampoo ingredients e.g. other surfactant material, foam boosters, dyes and perfumes.

The process of solubilisation is usually quicker when carried out in the presence of other surfactant material i.e. options (ii) or (iii) outlined above. The clear compositions made by the solubilisation procedures outlined as options (ii) or (iii) above may contain sufficient surfactant material so as to be used directly as a shampoo composition but normally other conventional shampoo ingredients will be added to these compositions before they are used as shampoos.

Whichever solubilisation technique is adopted the preferred procedure for achieving rapid solubilisation of useful quantities of pyridine-2-thiol-1-oxide salt is to add the pyridine-2-thiol-1-oxide salt in stages to an aqueous medium comprising the aqueous polynitrogen containing surfactant whilst the liquid is maintained at a temperature above the ambient.

The clear liquids formed by the solubilisation processes of option (i) above are completely miscible with water at neutral or alkaline pH's.

They can be incorporated into aqueous liquid shampoo compositions in a quantity sufficient for the pyridine-2-thiol-1-oxide salt to be effective as an anti-dandruff agent and these compositions are stabie over a pH range from 6.0 to 9.5 and temperature in the range of 0 to 850C.

The incorporation of a salt of pyridine-2-thiol-1oxide in an aqueous shampoo composition comprising inter alia certain polynitrogen based surfactants is proposed in British Patents 957458 and l, lit, 708 but in so far as the applicants are aware this particular combination has never previously been made.

Accordingly, from one aspect our invention provides a clear aqueous composition which comprises one or more of the zinc manganese magnesium calcium and iron salts of pyridine-2-thiol-1 -oxide and a polynitrogen based surfactant as hereinbefore defined. The salts of pyridine-2-thiol-1 -oxide have the formula:

wherein M is a divalent cation selected from the group comprising zinc, manganese, magnesium, calcium and iron.

The two formulae are tautomeric and any compound designated as a pyridine-2-thiol-1-oxide will inevitably comprise a mixture of the two.

From a second aspect our invention provides a clear aqueous shampoo composition which comprises a salt of pyridine-2-thiol-1 -oxide as hereinbefore defir.Fd, a sufficient quantity of a polynitrogen based surtactant to solubilise that salt together with a further quantity of a surfactant.

The efficiency of the solubilised salts of pyridine2-thiol-1-oxide as an anti-dandruff agent is increased as compared to that of the dispersed form of the corresponding salt. The finished shampoo product may therefore comprise less than the conventionally used quantities of these salts whilst retaining the same level of anti-dandruff activity or comprise a similar quantity of the salt thereby giving a product having a superior anti-dandruff activity.

In general the novel shampoo compositions of our invention will comprise from 0.05 to 3.0 per cent by weight of a salt of pyridine-2-thiol-1 -oxide. Preferably they will comprise from 0.1 to 2.0 e.g. 0.1 to 1.0 per cent by weight of these salts.

In orderto solubilise the salts of pyridine-2-thiol1-oxide it is preferable to add them to an aqueous medium comprising from 5 times to 500 times preferably 10 to 150 times the weight of these salts of a polynitrogen based surfactant as hereinbefore defined. The aqueous medium used in the mixing step preferably comprises from 1 to 80% most preferably from 5 to 25% by weight of the total surface active material.

The precise quantity of pyridine-2-thiol-1-oxide salt which can be solubilised in a particular medium varies according to the nature of the particular polynitrogen containing surfactant which is used as the solubilising agent. It is also dependent upon the relative proportion of water and surface active materials in the aqueous medium. Highly concentrated or very dilute aqueous solutions comprising the polynitrogen based surfactants are less effective in solubilising the pyridine-2-thiol-1 -oxide salts. Preferably aqueous media comprising from 5 to 25% by weight of polynitrogen based surfactant material are employed for the mixing step.

During the solubilisation process the pH of the medium is preferably maintained in the range 8.5 to 9.0 if necessary by addition of a suitable base.

The process of solubilisation can be carried out in the presence of excess quantities of surfactants. This excess provides the resulting composition with surfactant properties which enable it to be used e.g. as a shampoo composition or as a component of such a shampoo composition as outlined above. The finished shampoo composition may comprise anything from 2 to 80% by weight of surface active mat erial. There is thereby a large scope for carrying out the solubilisation in the presence of more active material than is necessary to solubilise the pyridine-2-thiol-1 -oxide salt.

This surplus of surface active material may consist of excess quantities of polynitrogen based surfac tants. However, we have discovered that the pres ence of other surfactants in the aqueous media aids the process of solubilisation.

The nature and quantity of surfactants used to provide this excess will be governed by the particu lar end-use to which the product is to be put.

Suitable auxiliary surfactants for incorporation into aqueous media aiong with the polynitrogen based surfactants as hereinbefore defined in order to provide the excess of surfactant material include all those known in the art. They may be anionic, cationic or amphoteric materials. Useful surfactants include all those described in Kirk-Othmers Encyclopaedia of Chemical Technology (1959 John Wiley & ons) Vol.

19 pages 512 to 566.

Especially useful surfactants include alkyl aryl sul phonates such as lithium, sodium, potassium, ammonium, or other water-soluble salts of su Iphonic acids of alkyl-substituted benzenes such as decyl toluene, dodecylxylene, octylbenzene, nonylbenzene, decylbenzene, tridecylbenzene, tetradecylbenzene, pentadecylbenzene, dodecylbenzene and hexadecylbenzene.

Olefin sulphonates such as water-soluble alkali metal and alkaline earth metal salts of mono or diolefin sulphonic acids comprising from 8 to 24 carbon atoms; alkali metal or ammonium alkyl sulphates in which the alkyl groups have from 10 to 18 carbon atoms and polyoxyethylenated and polyoxypropylenated derivatives thereof, alkali metal or ammonium salts of alkane sulphonates, alkali metal or ammonium salts of sulphosuccinate materials of the average general formula::

wherein m is from 0 to 25, R1 is hydrogen or a methyl group and R2 an alkyl group having from 8 to 25 carbon atoms, amine oxides such as those described in B.P. 943,353 having the formula R1R2R3NO, wherein R1 is an alkyl radical having from 9 to 25, preferably 10 to 16 carbon atoms and R2 and Rs are methyl or ethyl groups, and alkoxylated derivatives thereof.

Carboxybetaines of the general formula:

wherein R2 and R3 are alkyl or alkenyl groups containing from 1 to 6 carbon atoms and are preferably methyl groups, R4 is an alkylene group containing from 1 to 6 carbon atoms and R, is an alkyl or alkenyl group containing from 8 to 18 carbon atoms and corresponding sulphobetaines.

Amine oxides derived from amido-amines having the formula:

wherein R represents an alkyl or alkenyl group having from 8 to 20 carbon atoms. R, and R, are the same or different groups selected from hydrogen atoms, methyl or ethyl groups and n is an integer in the range 1 to 4, sulphates of the formula

wherein R, is an alkyl or alkenyl group comprising from 8 to 18 carbon atoms, R, represents a hydrogen atom or methyl group, R6 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a group (CH2CHR2O)2H andy and z which may be the same or different are integers having a value of from 1 to 70, our a group (CH2CHR2O)ySO3H wherein y is an integer having a value of from 1 to 70.

Polyoxethylene compounds of the general for mula RO(CH2CHR'O)xH where R is an alkyl, aryl, alkaryl, alicyclic, acyl, amino oralkylamino group; R' is hydrogen or an alkyl group having from 1 to 4 carbon atoms and x is from 3 to 100, usually from 6 to 50. Such compounds include fatty alcohol polyethoxylates, fatty acid polyethoxylates, polyethylene glycol ethers, mixed polyethylene and polypropylene glycol ethers, amine and diamine polyethoxylates, and fatty alkylolamide ethoxylates; fatty alcohol phosphates and polyethoxylated and polypropyloxylated derivatives thereof; fatty acid soaps.

Quaternary ammonium compounds having the formula:

wherein R1 represents an alkyl or alkenyl group having from 8 to 22 carbon atoms, R2 and R3 which may be the same or different represent an alkyl group comprising 1 to 4 carbon atoms, R4 represents an alkyl group having from 1 to 4 carbon atoms or a benzyl group and X represents a water solubilising anion such as chloride bromide or sulphate anion.

Particularly preferred compounds for use in the invention as auxiliary surfactants are the fatty alcohol phosphates and polyethoxylated and polypropoxylated derivatives thereof; the alkyl sulphates and polyoxyethenylated and polyoxypropyienated derivatives thereof; the alkyl betaines and sulphobetaines, the amine oxides and fatty acid alkanolamides especially the ethanolamides.

A preferred class of polynitrogen based surfactants for use in the novel shampoo composition are the so called imidazoline surfactants produced by the reaction of a carboalkylating agent with the N 2-alkyl-N-1-(2-hydroxyethyl)-2-imidazolines. These compounds are known to possess low eye and skinirritancy properties and are widely used as ingredients of shampoo compositions. Moreover, mixtures thereof with other surfactants also exhibit this property.

The most preferred imidazoline surfactants for present use are those which are produced by the reaction of an imidazoline having the formula:

wherein R represents a saturated or unsaturated alkyl or alkenyl group comprising from 8 to 20 carbon atoms, X represents hydrogen atom, a hydroxyl group or a carboxylate group and b is an integer having a value of from 1 to 8, with chloroacetic acid or a s-: thereof. Most preferably the imidazoline bases are those wherein b has a value of 2 and where X represents a hydroxyl group and these are reacted with chloracetic acid or a salt thereof.

The reaction is most preferably carried out in an aqueous medium at a temperature of from 40 to 90"C the pH of the reaction medium being maintained in the range 7.0 to 11.5 until at least 0.5 moles of carboalkylating agent per mole of imidazoline have reacted and thereafter the pH being maintained in the range 9.0 to 12.0. A maximum of 2.0 moles of carboalkylating agent per mole of imidazoline can be reacted using processes of this type and more usually between 1.7 and 1.8 moles of carboalkylating agent are reacted. The products comprise a mixture of non-carboalkylated mono carboalkylated and dicarboalkylated materials in which the noncarboalkylated material comprises less than 20 and preferably less than 10% by weight of the total weight of active material.The ratio of mono to dicarboalkylated material in the product is preferably in the range 1:2.0 to 1:0.2 and most preferably in the range 1:1.3 to 1:0.4.

The novel shampoo compositions of our invention may comprise from 1 to 80% by weight of surfactant (including that used to solubilise the pyridine-2 thiol-1-oxidesalt). Preferably they will comprise from 1 to 30 per cent by weight of a surfactant as hereinbefore defined.

The high cost of the polynitrogen based surfactants and the other nitrogen based materials described above means that compositions wherein they comprise the major proportion of the surface active material are correspondingly expensive. For reasons of cost it may be preferred where in particular a product having a relatively high irritancy to the skin or eyes can be tolerated to employ a major proportion of a less costly auxiliary surfactant as hereinbefore described. Such compositions still preferably comprise from 1 to 10% by weight of a polynitrogen based surfactant, and from 5 to 70% by weight of an auxiliary surfactant.

The compositions hereinbefore described comprising the solubilised pyridine-2-thiol-1 -oxide salts may be of such concentration e.g. comprising up to 25% by weight of active material has to be suitable for sale as ready for use formulations or they may take the form of high active concentrates comprising e.g.

up to 80% by weight of active material which are readily transported but which require dilution before use.

The invention is illustrated by the following examples: EXAMPLE I 320 g of Empigen CDR 10* and 80 g of water were weighted into a 600 ml beaker, and the temperature raised to 75"C with stirring, the heating being effected by means of a hot water bath.

6 g of the zinc salt of pyridine-2-thiol-1 -oxide (ZPTO) were then added to the mixture in a aliquots of 0.2 g, no aliquot being added until the preceding one had completely dissolved.

The temperature was maintained at 75"C, and stirring continued throughout the addition of the ZPTO.

The pH of the mixture was monitored throughout the addition of the ZPTO, and maintained in the range 8.5-9.0 by the addition of sodium hydroxide solution as required.

When all the ZPTO had been added, and a clear solution obtained, the product was cooled to ambient temperature and used to formulate shampoo compositions as follows: A B C Empigen CDRIO/ZPTO solution (wt.%) 30 25 30 Empicol ESB3 (we. %) 25 - Empicol LOX28* (wt. %) - 25 Empicol To40/1* (wt. %) - - 20 Empilan CD (wt. %) 2 2 2 Briphos 03 (wit. - - 2 Water (wt. %) 43 48 46 *EMPIGEN CDR 10 is an aqueous solution comprising the equivalent of 21% by weight of imidazoline base produced by treating 1 mole of coconut imidazoline of the formula::

with 2.5 moles of chloracetic acid for4 hours at a temperature of 55"C and a pH of 9.2 and thereafter raising the temperature to 700C and the pH to a value of 11.2 for a period of 15 hours (all pH's being measured as the pH of a 20% by weight solution).

The pH's of the products A, B and C were carefully adjusted to the range 7.0-7.2 with citric acid.

The resultant products were clear liquids, which remained clear on storage at 35"C and 0 C over several months.

* Empicol ESB3 is a 27.5% aqueous solution of sodium lauryl ethoxy sulphate comprising two ethylene oxide groups per molecule.

*Empicol LX28 is a 28% aqueous solution of sodium lauryl 10 sulphate.

* Empicol TL40T is a 40% aqueous solution of triethanolamine lauryl sulphate.

*Empilan CDE is a 100% coconut diethanolamide.

* Briphos 03D is a 100% phosphoric acid ester of an ethoxylated oleyl alcohol containing three ethylene oxide groups per molecule of alcohol.

EXAMPLE2 150 g of a 1/1 blend of Empigen CDRIO and a 28% aqueous solution of a sodium lauryl ether sulphate comprising three ethylene oxide groups per molecule, 6 g of Empilan CD and 143 g of water were weighed into a 600 ml beaker and heated to 70"C on a water bath with stirring. The pH was adjusted to between 8.5 and 9 and 0.9 gm of the zinc salt of pyridine-2-thiol-1-oxide (ZPTO) added in aliquots of 0.3 g, no aliquot being added until the proceeding one had completely dissolved.

The temperature was maintained at 70"C and the stirring continued throughout the addition of the ZPTO. The pH was maintained in the region 8.5-9.0 by the addition of sodium hydroxide solution as required.

When all the ZPTO had dissolved the solution was allowed to cool to ambient temperature, and the pH adjusted with citric acid to 7.0-7.2. A clear product which was indefinitely stable on storage at +5 C resulted.

Claims

1. A clear aqueous solution which comprises one or more of the zinc manganese magnesium calcium and iron salts of pyridine-2-thiol-1-oxide and a polynitrogen based surfactant as hereinbefore defined.

2. A composition according to claim 1, wherein the polynitrogen based surfactant is present in a quantity of from 5 to 500 times the weight of the salts of pyridine-2-thiol-1-oxide.

3. A composition according to claim 2, wherein the polynitrogen based surfactant is present in a quantity of from 10 to 150 times the weight of the salts of pyridine-2-thiol-1-oxide.

4. A composition according to any of the preceding claims which comprises from 1 to 80% by weight of the polynitrogen based surfactant based on the weight of water present.

5. A composition according to claim 4, which comprises from 5 to 25% by weight of the polynitrogen based surfactant based on the weight of water present.

6. A clear aqueous shampoo composition which comprises one or more of the zinc, manganese, magnesium calcium and iron salts of pyridine-2 thiol-1 -oxide, a sufficient quantity of a polynitrogen based surfactant as hereinbefore defined to solubilise that salt together with a further quantity of a sur facta nt.

7. A composition according to claim 6 which comprises from 0.05 to 3.0 per cent by weight of a salt of pyridine-2-thioi-1-oxide.

8. A composition according to claim 7 which comprises from 0.1 to 2.0 per cent by weight of a salt of pyridine-2-thiol-1 -oxide.

9. A composition according to any of claims 6 to 8 which comprises from 10 to 150 times the weight of the salt of pyridine-2-thiol-1-oxide of a polynitrogen based surfactant.

10. A composition according to any of claims 6 to 9 which comprises from 1 to 80% by weight of surface active materials.

11. A composition according to any of claims 6 to 10 which comprises sufficient polynitrogen based surfactant to solubilise the salt of pyridine-2-thiol-1 - oxide together with an additional quantity of surface active material.

12. A composition according to claim 11 wherein the additional quantity of surface active material comprises a surfactant selected from the group comprising fatty alcohol phosphates, and polyethoxylated and polypropoxyl ated derivatives thereof; alkyl sulphates and polyoxyethylated and polyoxyl propylated derivatives thereof, alkyl betaines and sulphobetaines, amine oxides and fatty acid alkanolamides.

13. A composition according to claim 12, wherein the additional surface active agent is a fatty acid ethanolamide.

14. A composition according to any of claims 6 to 13 which comprises from 1 to 10% by weight of a polynitrogen based surfactant.

15. A composition according to any of claims 11 to 14 which comprises from 5 to 70% by weight of an additional surface active agent.

16. A composition according to any of claims 6 to 15 which further comprises a foam booster, a dye or a perfume.

17. A composition according to any of the preceding claims wherein the polynitrogen based surfact has the formula:

where R represents a saturated or unsaturated alkyl or alkenyl group comprising from 8 to 20 carbon atoms, A represents a hydrogen atom or a group of the formula R3COO- wherein Ra represents a substituted or unsubstituted alkylene group having from 1 to 4 carbon atoms, X represents a hydroxy group Y represents a carboxylate group or a sulphonate group B represents an alkyl group comprising from 1 to 4 carbon atoms a and care integers having a value of from 1 to 3 and b represents an integer having a value of from 1 to 8.

18. A composition according to claim 17 which comprises a mixture of compounds wherein A represents a hydrogen atom with those compounds wherein A represents a group R3COO-.

19. A composition according to claim 18 wherein Ra represents a methylene group.

20. A composition according to either of claims 18 or 19 wherein the ratio of products, wherein A represents to hydrogen atom to those wherein A represents a group RaCOO is in the range 1:2.0 to 1:0.2.

21. A composition according to claim 20 wherein said ratio is in the range 1:1.3 to 1:0.4.

22. A composition according to any of claims 17 to 21, wherein a has a value of 2.

23. A composition according to any of claims 17 to 22 wherein b has a value of 2.

24. A composition according to any of claims 17 to 23, wherein c has a value of 1.

25. A composition according to any of claims 17 to 24, wherein Y represents a carboxylate group.

26. A composition according to any of claims 17 to 25, wherein A represents a group R3COO- and Ra represents a methylene group.

27. A composition according to any of claims 1 to 16, wherein said polynitrogen containing surfactant has been produced by the reaction of an imidazoline having the formula:

wherein R represents a saturated or unsaturated alkyl or alkenyl group comprising from 8 to 20 carbon atoms, X represents a hydrogen atom a hydroxyl group or a carboxylate group and b is an integer having a value of from 1 to 8 and chloracetic acid or a salt thereof.

28. A composition according to claim 27, wherein b has a value of 2.

29. A composition according to either of claims 27 or 28 wherein X represents a hydroxyl group.

30. A composition according to any of claims 27 to 29, wherein the reaction between the imidazoline and the chloracetic acid is carried out at a temperature of from 40 to 90"C and at a pH of from 7.0 to 11.5 until at least 0.5 moles of chloracetic acid per mole of imidazoline have reacted and thereafter the pH is maintained in the range 9.0 to 12.0.

31. A composition according to any of the preceding claims substantially as hereinbefore described with reference to the foregoing examples.