Topical Therapy and Formulation Principles

15 May

INTRODUCTION

Other  chapters have  discussed the biology  and  medical consequences of acne, and with  it the types  of actives  required to be delivered to resolve  them.  This chapter focuses  on  the  actives  and  the  delivery vehicle  used,  and  considers the  myriad types  of formulation available.

This is not  intended to be a truly  comprehensive and  in-depth study, since space does not permit it. Rather, it is designed to inform  and, hopefully, excite inter- est and  provide a starting platform for further investigation and  experimentation. Some guideline formulations will  be given,  but  there  are  other  sources  that  offer these  in greater number. Suppliers of raw  materials are  always valuable sources of starting formulary, some  of which  may  already have  undergone some  perform- ance testing.  As with all published formulae, the principle of caveat emptor applies, and   the  formulator  should  always confirm   that   the  product  performs to  the required standards.

The sections  within this  chapter are intended to form  the basis  of the infor- mation that  needs  to be generated in developing the product. Although this  may not  seem  relevant in  this  context,  the  risks  associated with  the  formulation are such  that  a wide  range  of proof  should be established. Some of this  is prescribed in legislation, and the requirements this imposes on formulations will be discussed.

Formulations are much  more  than  a simple  mix of chemicals with  long  and often  incomprehensible names. The formulation is the  long-term success  story  of a product in that:

B      It carries the active and ultimately determines whether or not the active delivers the desired benefits.

B      It can influence a user ’s desire  to continue using  the product to obtain  the full benefit  of the active.

B      For commercial products, persuading consumers to make  an  initial  purchase requires good  marketing; getting them  to purchase it a second time (and  hope- fully more)  requires a good  formulation.

It is important to note that the majority of topical  acne treatment products are commercial in nature, purchased directly from  a store  shelf or pharmacy counter. Consumer promotion and  advertising are  an  integral part  of this  market place, and  the  formulator of such  products must  be aware of and  take  into  account the demands of these  consumers.

Before a product can be considered fit for release  to the consumer, consider- ation  must  be given  to the following points:

B      Does the product meet the brief set by the marketing team and will it satisfy the end  consumer ’s needs?

B      Does  it conform to the  product description, advertising, and  any  claims  that may  be made?

B      Is it economically viable?

B      Does it infringe others’  intellectual property rights?

B      Is it safe for its intended purpose?

B      Is it stable  and  will  it remain fit for  the  purpose for  a reasonable length  of time?

B      Can  it be  manufactured reproducibly and  in  reasonable quantities to  satisfy consumer demand?

Failure  to satisfy  these  principles increases the risk of issues  arising  in the market place and, with it, potential harm to the user and commercial damage to the produ- cer. As with  many  things,  preparation is the key and  a clear strategy of how  these points will be addressed should be in place  before  the formulation is considered. Careful  planning, sound scientific  skills, and  a robust process  will ensure the ulti- mate  end  point—a successful product.

In treating acne, we are attempting to:

B      Clear existing  lesions  and  prevent the formation of new  ones.

B      Relieve  the  discomfort from  the  biophysical process   of  acne  formation and therapy.

B      Reduce  inflammation.

B      Minimize the negative psychological effects.

The physical/chemical activities that  the product will be attempting to deal with  are:

B      Reducing excess oil.

B      Controlling the bacteria  associated with  acne.

B      Reducing the effects of hyperkeratinization.

B      Unclogging pores.

The extent  of the condition will dictate  the type  of active  required:

B      Moderate-to-severe drug products, some  requiring a physician’s prescription.

B      Mild-to-moderate mixture of drug products that  do  not  require a physician’s prescription  and   more   cosmetic   products  from   a  range   of  producers,  for example,  Clearasilw   (Reckitt   Benckiser   Inc.,  New   Jersey,  U.S.A.),  Clean   & Clearw (Johnson  & Johnson  Corporation, New Jersey, U.S.A.), and Neutrogenaw (Neutrogena Corporation, California, U.S.A.).

The  formulator must   consider the  technical characteristics of  maintaining and delivering the drug active  alongside the need  for an elegant product that  the user will enjoy using.  Although this may sound incongruous, a product that is enjoyable to use is more likely to be used  as required and,  therefore, deliver the full benefit of the active.

Formulating the product, that is, putting a mixture of ingredients together, is only  the first stage  and  in doing  so the formulator must  always bear  in mind the basic  principles outlined earlier.   In  order to  do  that,  a  clear  understanding  of what  is required allows  a robust strategy to be developed, reducing time  wasted on unnecessary formulation.

FORMULATION STRATEGY

A  clear  brief  or  desired end   point   is  essential for  an  effective   strategy. Once obtained, there  are three  routes the formulator can take:

B      Modify  an existing  product with  a known history.

B      Use or modify a formulation obtained from the literature.

B      Devise  an entirely new  formulation.

The route  taken  will clearly  be dictated by a number of factors,  but  will include such  things  as the degree of risk the formulator is able to take and  the timescales in which  the product has to be delivered. The first route  is clearly the lowest  risk, as there  will be information on many  of the key factors  required for a successful development. The  second route  provides for  somewhat higher risk  in  that  the product may  not have  undergone a complete evaluation.

The final route  clearly has the highest risk but offers the greatest flexibility for incorporation of actives,  and  allows  for significant innovation. A clear view  of the intended application and  all claims  that  will be made about  the product are essen- tial. The starting point  will be the active, or actives,  and  the formulation should be built with the view to maximizing performance, safety, and stability. It is important to remember that  this  must  include end-user compliance; petrolatum may  be the best carrier  for a topical  active,  but  it would not be the most  likely  base to ensure continued  use.  The  complexity  of  factors   in  producing novel   formulations  is shown in Figure  1 (1).

FIGURE 1    There are clearly inter-related events that must be taken  into account when formulating new products. They are not mutually exclusive and it is important  to consider all possibilities  during the whole process of development. Source: From Ref. 1.

Acne treatments fall within three  major  regulatory areas:

B      Licensed  prescription or licensed over-the-counter (OTC) medicines.

B      Monographed OTC medicines.

B      Cosmetics.

Regulations exist  in all countries concerning most,  if not  all, of these  three  areas. Although somewhat easier in the European Union  (EU), where there is harmoniza- tion of regulations, formulators should confirm  that  the ingredients used  and  pro- ducts  produced comply  with local regulations, especially where they are likely to be sold in different countries. While the International Conference on Harmonization of Technical  Requirements for Registration of Pharmaceuticals for Human Use (ICH) has attempted to introduce a degree of harmonization in certain  areas, it should be remembered  that   products considered drugs  in  one  country are  cosmetics in another.

Even with increasing harmonization, formulators should be aware of the local regulatory status of their  product as this may  affect:

B      The type  of claims  that  can be made.

B      The status of certain  ingredients such  as sunscreens, colors,  preservatives, and herbal  extracts  in terms  of ability  to use and  level.

B      The  statutory warnings that  require displaying for  the  product, actives,  and excipients.

B      The quality standards of the actives  and  excipients used  in the formulation.

B      The type  and  extent  of the testing  required to bring  the product to market.

Regulations constantly change  and  formulators require up-to-date knowledge on the legal requirements and the implications that these may have on the formulation of topical  acne products.

In  the  next  section,   the  range   of  technologies  available  for  use  will  be discussed.

PRODUCT  TYPES

There are six major technology areas that formulators may wish to utilize,  as shown in Table 1.

Emulsions

An    emulsion   is   a   dispersion   of   two    immiscible   liquids   in    the    form of droplets. The  majority of emulsions fall  into  one  of two  types,  as  shown in Figure  2.

The following general characteristics of emulsions are displayed in Table 2. Emulsions are thermodynamically unstable, which  means they are always attempt- ing  to  return to  their  natural, single-phase states.  This  is overcome through the addition of energy  in two  forms:

B      Mechanical energy  through the use of high  shear  mixers.

B      Chemical energy  through the use of emulsifiers.

In practice, both  forms  of energy  would be used  to deliver a longer-term stable product.

Note: The range of products available  for use  is wide, and careful consideration should be given to the best  type to achieve maximum  active  delivery and good  patient  compliance.

Emulsifiers are  materials that  have  an  affinity  for  both  the  oil  and  water phases, and  as such,  sit at the interface of the two  phases. There  are a number of types,  as shown in Table 3.

Anionic  emulsifiers have  increasingly become  replaced by nonionic systems, as they offer the formulator much  greater flexibility  in terms  of range,  end product characteristics, mildness, and  compatibility with  actives.  Cationic  emulsifiers are only rarely  used.

With the myriad of emulsifiers that are available for the formulator, the choice is not an easy one. Considerations such as compatibility with actives and excipients and  finished product stability are clear priorities, but significant thought should be given  to ease  of use  (both  in terms  of laboratory and  large  scale),  safety  profile, supply chain  and,  of course,  price.

For systems in which  the formulator has decided to use nonionic emulsifiers, help  is available in deciding the  type  of emulsifier. Known as the  Hydrophilic – Lipophilic Balance  (HLB) system, it gives  the  formulator an  indication (within a

given molecule) of the balance between affinity for oil and water. HLB uses a simple numbering system to  indicate the  relative   balance.   In  the  system, 1 represents highly  lipophilic (oil-loving) and  20 represents highly  hydrophilic (water-loving). Figure  3 illustrates how  this is achieved in practice.

The  HLB  number is  determined  experimentally by  producing emulsions with  oils  of  known HLB,  or  by  theoretical calculation based   on  the  chemistry of the molecule. A blend  of high  and  low HLB emulsifiers will generally be more effective  than   a  single  emulsifier that  yields   an  equivalent HLB,  as  illustrated in Figure  4.

The types  of oils used  in the  formulation will  determine the  required  HLB number. Formulators need  to consider the type  of emulsion they  are intending to make  as this  can  affect the  choice  of emulsifier system required. For example, to emulsify Paraffinium Liquidium (2):

Required HLB for oil in water:     10  12

Required HLB for water in oil:         4  5

The choice  of oils will  be determined by the  desired texture of the  finished product. Such blends are determined by trial and error until optimum product per- formance is  achieved. Other   ingredients that  might   form  part  of  the  emulsion system  include  humectants,  water  phase   thickeners,  such   as   carbomer and xanthan gum,  preservatives, and  fragrance.

Surfactant Systems

An important part  of acne treatment is ensuring that the affected  area is kept clean. This product category is clearly important in achieving this objective. Although the emulsifiers, described in the previous section, are surfactant in nature, their concen- tration is significantly lower  than  that  found in many  washing products such  as shampoos and  shower gels.

FIGURE 3    Nonionic  emulsifier,   Cetearyl Glucoside [Tegow   Care   CG90   (Goldschmidt  GmbH, Essen,   Germany)], illustrating   the   balance  between  hydrophilic   and   lipophilic  entities.   The Hydrophilic – Lipophilic Balance of this molecule  is 11+1 and  by manipulating the  number  of units on  either  side,  changes the  balance and  with it the  likelihood of being  able  to produce different emulsion  types. Source: Diagram  courtesy Degussa Goldschmidt Personal Care.

The classification given  in Table 3 remains applicable here,  although Table 4 indicates the relative  merits  of these  materials for this application.

The  primary purpose  of  surfactant products  in  acne  applications  is  the removal of  surface   oils.  While  it  is  possible to  add   active  ingredients to  such systems, formulators  must   remember that  they  are  wash-off products  and  the degree of deposition of active  can vary.

Formulating surfactant products is not  simply a matter of maximizing the level  of surfactant. Even  in oily skin,  excessive  defatting remains a problem, and the   balance   between  cleanliness  and   drying/irritation  should  be  taken   into account. Due  to  their  nature, surfactants tend   to  form  the  micellular structure shown in Figure  5.

This is an important property as it helps  to explain the mechanism by which the  products remove oil  and  prevent re-deposition. The  surfactant reduces the surface  tension of the  oil on the  skin,  allowing dispersion of the  unwanted oil in the surfactant system. The lipophilic core of the micelle  is where the oil is held.

Formulators must  also be aware of the reverse happening with  a detrimental effect on product performance. Such situations may occur where actives have signifi- cant affinity  for the surfactant micelle, and  the active ingredient becomes  effectively trapped and  is removed on  rinsing. This  is most  likely  to  occur  with  lipophilic actives,  or in anionic  systems with  small  cationic  materials due  to charge  coupling.

There is a range  of anionic  surfactants that  the formulator may consider. The most popular is based  on alkyl ether  sulfates, such as sodium or ammonium lauryl ether  sulfate.  The extent  of ethylene oxide  addition determines the overall  proper- ties of the surfactant. Two or three  units  are the most  common format  combining good  surfactancy; ammonium salts  produce richer  creamy  foam  than  the  more open  but  equally copious sodium version. For the equivalent degree of ethoxyla- tion,  magnesium salts  show  more  mildness than  their  sodium counterpart and increasing the  number of  ethoxylated units   also  increases mildness  (3).  Alkyl ether  sulfates provide the  backbone to many  wash  products, given  their  ease  of handling, wide  range  of stability, and  cost.

Other  commonly used  primary surfactants include those  from groups such as sarcosinates and sulfosuccinates. These ingredients offer greater mildness (3) and con- ditioning than alkyl ether sulfates, but their cost-performance ratio has not led to their

extensive use. In normal circumstances, product viscosity  can be raised through the controlled addition of a compatible electrolyte. This group of surfactants does  not easily  lend  itself to this  method and  alternative means of thickening, for instance, the use of materials such as PEG-55 propylene glycol oleate need  to be considered.

A  further way  to  enhance the  characteristics of the  primary  surfactant is through the use  of secondary surfactants such  as amphoteric betaines and  amine oxides.  The  most  common of this  class  used  is cocamidopropyl betaine, which enhances foam  quality and  provides some  form of skin conditioning.

Although many  nonionic surfactants are equally effective at removing excess oils, they  are not widely used  as primary materials in this medium. The reason is their   poor   foam   production  that   most   consumers  associate  with   an  effective product. More commonly found playing a secondary role, many  nonionic products can enhance foam stability, leave a good  skin feel, and  may also have  a thickening effect for the products. Among commonly used  nonionics are sugar-based gluco- sides  such  as Decyl Glucoside, alkoxylated amides such  as PEG 5 Cocamide, and alkanolamides such  as Cocamide DEA.

If using diethanolamines such as Cocamide DEA, the formulator must use high- purity material and avoid using nitrating agents to prevent formation of nitrosamines.

A wide  range  of additional materials are  found in  surfactant systems, as shown in Table 5.

Solutions

While solutions are the simplest and  easiest  to produce formulation, consideration must  be given to the way in which  the end user will use the product and, therefore, whether this is the most  effective  format  for delivering actives  and  benefits.

The major  advantage of using  solutions is the range  of individual and  mix- tures  of polar  and  nonpolar solvents that  are  available to  the  formulator from water through to oils. Due  to the simplicity of many  solutions, formulation inter- actions  can  be  more  carefully managed than  in  more  complex systems such  as emulsions.

There has been an increasing trend toward the use of wipe  products that con- sists of a fibrous  cloth soaked in a suitable solution. The formulator preparing sol- utions for this type of application must  bear in mind the possible interactions with the cloth and  the way in which  the wipes  will be used.  This is important for packs offering  multiple wipes  that  allow  the user  to reseal  the pack  after  each  removal. When  choosing the solvent, the formulator should consider whether the volatility of  their   chosen   solvent  might   cause   unacceptable  changes  in  the   level   and

availability of the  active.  This  may  manifest itself  in two  ways.  First,  the  loss  of solvent may  increase the  concentration of active  above  the  legally  allowed level, or above  the level at which  it remains safe. Second,  for crystalline solutes  (which may  or may  not  include the  active),  loss  of solvent increases the  risk  of precipi- tation.  This  may  result  in  injury  to  the  end  user,  particularly if the  product  is intended for use around the eye area.

Gels

Gel formulations are particularly useful  in acne treatments as they  offer the possi- bility  of delivering active  ingredients in a totally  oil-free  manner. The majority of formulations will be water, alcohol, or mixtures of these materials, but formulators need  to be aware that it is possible to gel oils, although this is unlikely to be used  in this  application. The exception to this  is ointments, which  it could  be argued, are thickened oils,  but  the  formulation of  ointments is  more  complex and  is  dealt with  in a later  section.

In its simplest terms,  a gel is a thickened solution, although the differing rheo- logical qualities of gels from solutions offer formulators the possibility of improving application and  ensuring better  control  of coverage than  for solutions.

Carbomers are acrylic acid polymers available in a variety of grades, offering formulators a range  of viscosities and  textures with  defined yield points that allow excellent  spreading and  rapid absorption during use.  Standard grade carbomers lose  viscosity  in  the  presence of electrolyte, although hydrophobically modified grades with  improved electrolyte tolerance are available. Due  to the need  to neu- tralize  carbomers to  achieve  the  gel  structure, the  range   of actives  that  can  be used  is reduced compared with  other  gellants.

Xanthan gums  are  polysaccharides with  high  molecular weight that  show much  greater stability toward electrolytes. They have excellent  suspending proper- ties due to their pseudoplastic rheology. They will not produce clear gels easily and they  are not as rapidly adsorbed onto the skin as carbomers.

Modified cellulose  gums  are similar in their  chemistry to xanthan gums,  but clear gels can be produced with certain  grades. With a more lubricious feel than car- bomers, they can be used  on their own or in combination with carbomers to extend rub-in  time.

Silicate  systems are  available from  both  natural and  synthetic sources.  The synthetic  material  produces  clear  water  white   gels  that   can  be  stabilized  to produce products over  a very  wide  pH  range.  Due  to their  anionic  nature, they are incompatible with  cationic  materials.

Ointments

Although consumers may  classify  these  products and  creams  as the same  for the purpose of this  section,  an ointment is considered to be an oil base  only  with  no water present. While  this  may  seem  unusual for a condition where excess oil is a major  cause  of the  problem, as  will  be  seen  later,  water-free conditions may  be required to provide the best environment for the active.

Ointments, due  to their  oily nature, can be difficult  to remove and  leave  the skin  feeling  greasy.  For this  application, formulators may  consider the  ointment to  be  the  oil  phase  of an  as  yet  unfinished emulsion, where the  water used  to wash   the  product off  forms  the  final  piece.  Careful   choice  of  ingredients  will improve the  rate  of removal and  with  it the  after  use-skin feel. As always, there

is a balance, in this case, between the desire for effective removal and the risk of irri- tation  from  the  emulsifiers. There  are  a number of emulsifiers that  offer  a low irritation potential and  their ability to form emulsions at low temperatures, includ- ing the polysorbate group.

Soap

Soap remains one of the most widely used  personal washing products, and  formu- lators  should not  discount this  fact  when considering topical  treatments. Soap, while  it has  excellent  cleansing properties, does  not  lend  itself  to efficient  active delivery. The two  major  drawbacks with  soap  are that  it is washed off and  so the active  concentration deposited may  be small  and  its high  pH  can degrade certain actives,  and  cause  a lower  tolerability on more  sensitive skin.

Alternatives to  soap  are  Combi  bars  (combinations of soap  and  synthetic detergents) or  Syndet   bars,  based   wholly on  synthetic detergents. Syndet   bars offer the formulator more  flexibility  in that  their  pH  is lower  and  can be modified by allowing a wider range  of actives  to be used.  Soap, Combi,  and  Syndet  formu- lations  require specialist knowledge and  equipment, and  a number of companies offer contracted services  in this area.

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