ACTIVE RAW MATERIALS

15 May

Retinoids
In this  section,  the range  of materials being  considered may  be seen  described as retinoids, retinoid types,  or retinoid prodrugs. The appropriate description to use will  depend on the  individual compound being  considered, but  all the  materials are used  in topical  treatments for acne, and  are described in more detail  elsewhere.

Retinoids are highly active, and from a formulator ’s viewpoint, often unstable compounds being affected variously by light, heat, and oxygen. There are a number of compounds that  fall within this classification, including:

B      Tretinoin, [Retin Aw (Johnson  & Johnson  Corporation, New  Jersey, U.S.A.)]

B      Isotretinoin, [Accutanew  (Hoffman-La Roche Inc., New  Jersey, U.S.A.)]

B      Adapalene, [Differinw (Galderma S.A., Lausanne, Switzerland)]

B      Tazarotene, [Tazoracw (Allergan Inc., California, U.S.A.)]

For many,  use in actinic  lighting conditions should be avoided, and  the raw material and  finished product storage vessels  should be  flushed with  nitrogen after  use.  In emulsion products, care  should be taken  during manufacture, both to  avoid   excess  heat   and   to  minimize  incorporation  of  air  that   may   lead   to longer-term stability problems.

Retinoids are  generally insoluble in  water, but  have  varying solubility in alcohol,  other  solvents, and  oils.

Products should be packed for storage and consumers in protective materials such  as amber  glass, metal,  or plastic  laminated tubes.

Benzoyl Peroxide

The clinical effectiveness of benzoyl peroxide is well-established and  is discussed elsewhere. Benzoyl  peroxide is  a  highly   effective  oxidizing agent,   and  contact should be avoided with  reducing agents, metals  (particularly transition metals), and  organic  materials to prevent the  risk  of fire and  explosion. Peroxides break

down when heated and are capable of rapidly continuing their decomposition even if the heat  source  is removed.

Insoluble in water and barely soluble  in other  solvents, it can most commonly be found in emulsion and  gel formats. Ensuring adequate and  equal  dispersion throughout the  formulation is critical.  Milling  with  a colloid  mill  or  high-shear mixers  should be  undertaken  carefully to  avoid  high  levels  of heat  generation. Mixing   equipment should be  of  stainless steel  manufacture and   no  transition metals,  for example, copper collars, should be in contact  with the product. Alterna- tively, benzoyl peroxide is dispersed well in a small  amount of cooled  bulk, under more  controllable conditions before adding to the remainder of the product.

Products should be packed in airtight containers to maximize product  life. Examples of products in use with  this material include:

B      Clearasilw  Maximum Strength

B      Benzac ACw Wash  (Galderma Laboratories L.P., Texas, U.S.A.)

B      Panoxylw (Stiefel Laboratories Inc., Florida,  U.S.A.)

Table 6 shows  an example of a cream  containing benzoyl peroxide.

Salicylic Acid

The clinical effectiveness of salicylic  acid is well-established and  is discussed else- where. Salicylic acid is a white crystalline powder showing slight solubility in water but being freely soluble  in alcohol. Salicylic acid is most active in its acid form, and formulators should use suitable buffer solutions in formulations to maintain the pH between 2 and  4.

Salicylic acid  can be found in most  of the formats described earlier  under a number of brands, for example, Clearasilw, Clean  & Clearw, and  Neutrogenaw.

Antibiotics

There  are  a variety of antibiotics used  for  topical  applications and  these  include Tetracyclines  and   Macrolides  such   as  Erythromycin. Although  they   each  have unique physical properties and  solubility, a  common feature is  their  stability in aqueous  solutions. It  has  been  suggested that  antibiotics such  as  erythromycin show  increased loss of anti-microbial activity,  over  time,  although this  varies  with product base (4). Varying pH can change  this loss of activity, but, for products requir- ing extended shelf life of greater than  a few weeks,  alternative solvents or systems should be considered. Antibiotics are also adversely affected  by heat and  light.

For  topical  application gels,  alcoholic  solutions or  ointments are  the  most commonly produced formats. Examples include:

B      Akne-Mycinw [Erythromycin (Hermal Kurt Hermann GmbH, Reinbek, Germany)]

B      Cleocin  Tw  [Clindamycin (Pharmacia & Upjohn Company LLC, New  Jersey, U.S.A.)]

B      Topicyclinew  [Tetracycline (Shire LLC, Pennsylvania, U.S.A.)].

Resorcinol

Resorcinol is colorless  to slightly pink – grey  and  is very  reactive to light  and  air, turning red  when oxidized.

The effectiveness of resorcinol has  been  recognized and  claims  that  can  be made through the use of this material are available (5).

Due to its good solubility in water and alcohol, resorcinol can be incorporated into a wide  range  of products, including emulsions, being  stable  to heat  at normal emulsification temperatures and  times.  Manufacturing under vacuum reduces the risk of loss of activity,  and  products containing this  material should be packed in materials with  good  oxygen  barriers.

Examples of products containing resorcinol include Clearasilw  Adult Carew

Acne Treatment Cream.

Sulfacetamide

Sulfacetamide has  been  widely utilized for its antibacterial properties for a con- siderable period of time.  In the sodium form,  it is a white  to off-white crystalline substance showing good  solubility in water but reduced solubility in alcohol.

This material can be found in a 10% form in Klaronw (Aventis Pharmaceutical Inc., New Jersey, U.S.A.). Sulfacetamide has also been shown to be effective in com- bination with  sulfur (6).

Azelaic Acid

Azelaic acid was first licensed for use in the United States in the late 1990s for mild- to-moderate inflammatory acne. While its exact mode  of action  remains unclear, it

has  antimicrobial properties and  is active  in reducing hyper keratinization. It has been reported to be active in a number of areas, including against hyper pigmenta- tion, so there  may  exist a risk of skin lightening (7). Studies  have  suggested that  it has similar activity  to other  active  agents (8).

Azelaic acid is soluble in boiling water and alcohol and is, therefore, able to be formulated into a range  of different product types.

Products containing this material include Azelexw (Allergan Inc., California, U.S.A.) and  Finevinw (Schering  Aktiengesellschaft, Berlin, Germany).

Sulfur

Sulfur  is a yellow  powder with  a characteristic odor  and  should be stored away from light. It is practically insoluble in water, but shows  some solubility in vegetable oils.

Due to its lack of solubility, sulfur must  be well-dispersed. High-shear mixing appropriate for dispersing powders or making pastes prior  to incorporation in the remainder of the formulation should be considered.

As it is a powder, the overall  stability of the product will depend on the effec- tive maintenance of the dispersion. This may be achieved through the appropriate choice  of formulation and  a good  understanding of the  rheology of the  system to prevent migration and  agglomeration of the powder. Although it may be accep- table  to  allow  the  consumer to  remix  the  formulation through  the  process   of shaking, the  formulator should ensure that  adequate dispersion is  maintained throughout the shelf life of the product. Although not commonly used, products uti- lizing sulfur include Stiefelw  Sulfur Soap (Stiefel Laboratories Inc., Florida,  U.S.A.).

Sulfur  is often used  in combination with  other  ingredients, for example:

B      With  resorcinol in  products such  as  Clearasilw  Adult Carew  Acne  Treatment

Cream

B      With  sulfacetamide in Sulfacet – Rw  (Aventis Pharmaceuticals Inc., New  Jersey, U.S.A.).

Table 7 shows  an example formulation utilizing sulfur and  resorcinol.

STABILITY

Stability  trials  are used  to identify problems that  may  affect the long-term quality and  safety  of the product. Due to the nature of the products under test, a number of  testing   regimes  are  possible.  In  this   context,   a  distinction  will  be  drawn between licensed (whether  via  prescribing requirements, monograph status, or OTC)  and  nonlicensed, where the  product claims  and/or  ingredients are  such that  the product is more  cosmetic  in nature.

Informal Testing

During the normal course  of product development, informal testing  will be under- taken. This will normally be carried out at a limited number of locations not necess- arily used  for formal  stability testing,  for example, freeze-thaw testing.  Testing  may be undertaken in glass to allow easy visual assessment of formulation instability, for example, separation, discoloration. Active  analysis may  be performed, but  is not the main  focus of this testing.

Formal Stability Testing

Prescribed, Monographed, and  Over-the-Counter Drugs

For  the  purposes of this  section,  drug products are  considered to  be  those  that contain either  drugs that must  be prescribed by a physician or, in certain  countries, by virtue of a monograph or OTC.

Where products are drugs, there are clear reasons for stability testing  in a way that  conforms to the ICH guidelines in place  for drug products (9). These define:

B      Number of batches  to be tested

B      Site of batch  manufacture

B      Testing  protocols

B      Degree  of testing

B      Shelf life allocation

ICH guidelines are updated on a regular basis, and  formulators should use a stability-testing regime that  conforms to the latest  requirements.

Active   ingredients  are  quantified  by  analysis  using   validated  analytical methods and  organoleptic assessment of the product for each temperature location at each time interval. Samples are removed from test and  not replaced.

Due to the nature of the product, sign-off  for sale and  allocation of shelf life should be by an appropriately qualified person, as defined by the  relevant legis- lation  applicable in the country of intended sale.

Nonlicensed Products

There  are no clear rules  for stability testing  of nonlicensed (Cosmetic) products at present. These  products will be considered in the same  way  as mentioned earlier, that  is:

B      Number of batches  to be tested

B      Site of batch  manufacture

B      Testing  protocols

B      Degree  of testing

The  products to  be  formally tested will  be  determined by  the  degree  of novelty. Where  products have  been developed from existing  products, it is concei- vable  that  only  one  laboratory-produced batch  would be tested, but  it is always good  practice to carry  out production trials  and  test samples generated.

An assessment should be carried out to determine the areas that would present most risk to the product stability. A typical  testing  regime is illustrated in Table 8.

Microbiological testing  should also be carried out at regular intervals. Organoleptic testing   would be  the  main  test  that  is  carried out,  although it  is prudent to carry  out  analysis for the presence of raw  materials, where significant claims  have  been  made. Sign-off  for  sale  and  allocation of shelf  life  should be done  by someone who  has sufficient  experience and  knowledge to make  an objec- tive assessment of the risk of this product failing  to conform to its specification, or causing harm for its likely shelf life, and  to conform to local regulation.

SAFETY EVALUATION

Safety  of the  finished product is a primary objective  of the  formulator. Consider- ation  of the safety of the product should be an iterative process  with  consideration and  review  at all stages  of the product’s development.

Safety assessment takes  place  at three  levels:

B      Assessment of  formulation raw  materials and  existing   formulation adverse event/sales ratio

B      Initial  evaluation of the formulation to assess  need  for safety  testing

B      Assessment of formulation for suitability for in vivo trial or sale

New raw materials or materials being used in a novel way should be screened for potential safety issues.  This will include detailed scrutiny of the Material Safety Data Sheet (MSDS), and the formulator should always discuss the implications with an expert  in the field such as a toxicologist or medical practitioner. For licensed pro- ducts,  new  raw  materials (drugs and  excipients) will  require a full  toxicological package to be provided to the appropriate regulatory body.

A record  of adverse events  that  may  have  an impact on the safety  should be maintained on all products sold. In some countries, this is a mandatory requirement and  forms  good  practice if it is not. This serves  two purposes:

B      It allows  ongoing assessment of the safety  of the product to be made

B      It provides a means by which  existing  formulations can be assessed for safety before further development

The figures  stored within the  database should be used  with  the  number of products sold  to determine the  degree of the  potential problem and  whether the base  could  be used.  Monitoring of existing  formulations allows  reformulation to be rapidly undertaken, should adverse events  rise  to an  unacceptable level.  All reports related to safety  issues  should be investigated further, as it is important that  only true  adverse reactions are considered.

If a  formulation is  judged to  be  different from  known base  formulations, safety  testing  should be carried out. These may  take the following forms:

B      In vitro tests for example:

.  3-D human skin model  to measure the effects on cell viability.

.  3T3 NRU  photo toxicity  test  to measure the  number of cells that  survive after  exposure to  the  test  chemical   and   UV  light,  compared with   the number that  survive after  exposure to the  chemical  in the  absence  of UV light.

B      Transcutaneous electrical  resistance (TER) procedure to measure skin corrosiv- ity through electrical  properties.

B      Repeat  Insult  Patch testing  on human volunteers to assess the irritancy potential of the formulation. Such studies should always be undertaken under the super- vision  of medical practitioner and  with  appropriate ethical  approval.

B      A user  trial (controlled or uncontrolled) on a group of people.

Once  the  testing   is  complete, the  product should be  assessed  to  decide whether it is safe for sale. This may  involve  submission to a regulatory authority.

For products where this is not the case, assessment should be made by a suit- ably   qualified  and   experienced  assessor.  There   are  published guidelines and requirements in certain  countries as to the qualifications needed by these  individ- uals  (10,11). Formulators should always ensure that  local  regulations regarding this important aspect  of developing a new  product are met.

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