14. chapter iv- review of drug, plant & excipients.pdf

Review of Drug,

Plant &

Excipients

CHAPTER IV

4.0. REVIEW OF DRUG, PLANT & EXCIPIENT

4.1. DRUG PROFILE- LEFLUNOMIDE

Leflunomide is classified as a Disease Modifying Anti Rheumatoid drug (DMARD).106-

108

Chemical name

N-(4´-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide.

Molecular formula

C12H9F3N2O2

Molecular weight

270.2

Structural formula

Indications

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (Fig.:

3)

1. To reduce signs and symptoms

2. To inhibit structural damage as evidenced by X-ray erosions and joint space

narrowing

3. To improve physical function

Fig. 3: Arthritic joints showing inflamed membrane and eroded cartilage

DOSAGE AND ADMINISTRATION

Loading dose

It is recommended that leflunomide therapy be initiated with a loading dose of a 100

mg tablet per day for 3 days.

Maintenance therapy

Daily dosing of 20 mg is recommended for treatment of patients with RA.

Adverse reactions

Diarrhoea, elevated liver enzymes (ALT and AST), alopecia and rash.

Drug abuse and dependence

Leflunomide has no known potential for abuse or dependence.

DRUG INTERACTIONS

In-vivo drug interaction studies have demonstrated a lack of a significant drug

interaction between leflunomide and tri-phasic oral contraceptives and cimetidine.

In-vitro studies of protein binding indicated that warfarin did not affect protein binding.

At the same time it was shown to cause increase ranging from 13 - 50% in the free

fraction of diclofenac, ibuprofen and tolbutamide at concentrations in the clinical

range. In-vitro studies of drug metabolism inhibit CYP 450 2C9, which is responsible

for the metabolism of phenytoin, tolbutamide, warfarin and many NSAIDs. It also

inhibits the formation of 4´-hydroxydiclofenac from diclofenac in-vitro.

Methotrexate

Co administration of leflunomide (100 mg/day x 2 days followed by 10 - 20 mg/day)

with methotrexate (10 - 25 mg/week, with folate) demonstrated no pharmacokinetic

interaction between the two drugs. However, co-administration increased risk of

hepatotoxicity.

Hepatotoxic drugs

Increased side effects may occur when leflunomide is given concomitantly with

hepatotoxic substances. This is also to be considered when leflunomide treatment is

followed by such drugs without a drug elimination procedure.

NSAIDs

In in-vitro studies, the metabolite was shown to cause increased ranging from 13-50%

in the free fraction of diclofenac and ibuprofen at concentrations in the clinical range.

Tolbutamide

In in-vitro studies, the metabolite was shown to cause increased ranging from 13 - 50%

in the free fraction of tolbutamide at concentrations in the clinical range.

Rifampin

Following concomitant administration of a single dose of leflunomide to subjects

receiving multiple doses of rifampin, the metabolite peak levels were increased (~40%)

over those seen when leflunomide was given alone. Because of the potential for

leflunomide levels to continue to increase with multiple dosing, caution should be used

if patients are to be receiving both leflunomide and rifampin.

WARNINGS

Hepatotoxicity

Severe liver injury, including fatal liver failure has been reported in some patients

treated with leflunomide. Patients with pre-existing acute or chronic liver disease or

those with serum alanine aminotransferase (ALT)>2xULN before initiating treatment,

should not be treated with leflunomide. Use with caution when leflunomide is given

with other potentially hepatotoxic drugs. Monitoring of ALT levels is recommended

atleast monthly for six months after starting leflunomide and thereafter every 6-8

weeks.

Immunosuppression potential/Bone marrow suppression

Leflunomide is not recommended for patients with severe immunodeficiency, bone

marrow dysplasia or severe uncontrolled infections. In the event that a serious infection

occurs, it may be necessary to interrupt therapy with leflunomide and administer

cholestyramine or charcoal.

Skin reactions

Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been

reported in patients receiving leflunomide. If a patient taking leflunomide develops any

of these conditions, leflunomide therapy should be stopped and a drug elimination

procedure is recommended.

Malignancy

The risk of malignancy particularly lymphoproliferative disorder is increased with the

use of some immunosuppressant medications.

Use in women of childbearing potential

There are no adequate and well-controlled studies evaluating leflunomide in pregnant

women. However, based on animal studies leflunomide may increase the risk of fetal

death or teratogenic effects when administered to a pregnant woman.

Peripheral neuropathy

Cases of peripheral neuropathy have been reported in patients receiving leflunomide.

Most patients recovered after discontinuation of leflunomide but some patients had

persistent symptoms. Age older than 60 years, concomitant neurotoxic medications

and diabetes may increase the risk for peripheral neuropathy. If a patient taking

leflunomide develops a peripheral neuropathy, leflunomide therapy should be

discontinued and the drug elimination procedure should be adopted.

Drug elimination procedure (less than 0.02 mg/L or 0.02 µg/ml) after stopping

treatment with leflunomide:

1. Administer cholestyramine 8 grams 3 times daily for 11 days (the 11 days do

not need to be consecutive unless there is a need to lower the plasma level

rapidly)

2. Verify plasma levels less than 0.02 mg/L (0.02 µg/ml) by two separate tests at

least 14 days apart. If plasma levels are higher than 0.02 mg/L additional

cholestyramine treatment should be considered. Without the drug elimination

procedure, it may take upto 2 years to reach plasma metabolite levels less than

0.02 mg/L due to individual variation in drug clearance.

PRECAUTIONS

General

Need for drug elimination

The active metabolite of leflunomide is eliminated slowly from the plasma. If

hypersensitivity is the suspected clinical mechanism, more prolonged cholestyramine or

charcoal administration may be necessary to achieve rapid and sufficient clearance. The

duration may be modified based on the clinical status of the patient. Administration

of activated charcoal (powder made into a suspension) orally or via nasogastric tube (50

g every 6 hours for 24 hours) has been shown to reduce plasma concentrations of the

active metabolite, by 37% in 24 hours and by 48% in 48 hours. These drug elimination

procedures may be repeated if clinically necessary.

Respiratory

Interstitial lung disease has been reported during treatment with leflunomide and has

been associated with fatal outcomes. The risk of its occurrence is increased in patients

with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal

disorder, which may occur acutely at any time during therapy and has a variable clinical

presentation. New onset or worsening pulmonary symptoms, such as cough

and dyspnea with or without associated fever may be a reason for discontinuation of the

therapy and for further investigation as appropriate. If discontinuation of the drug is

necessary, initiation of wash-out procedures should be considered.

Tuberculosis reactivation

Prior to initiating immunomodulatory therapies including Leflunomide, patients should

be screened for latent tuberculosis infection with a tuberculin skin test.

Renal insufficiency

Single dose studies in dialysis patients show a doubling of the free fraction of

metabolite in plasma.

Vaccinations

No clinical data are available on the efficacy and safety of vaccinations during

leflunomide treatment. Vaccination with live vaccines is however not recommended.

Blood Pressure monitoring

Blood pressure should be checked before start of leflunomide treatment and

periodically thereafter.

OVERDOSE

There have been reports of chronic overdose in patients taking leflunomide at daily

dose upto five times the recommended daily dose and reports of acute overdose in

adults or children. There were no adverse events reported in the majority of case reports

of overdose. Adverse events were consistent with the safety profile for leflunomide.

The most frequent adverse events observed were diarrhea, abdominal pain,

leukopenia, anemia and elevated liver function tests. In the event of a significant

overdose or toxicity, cholestyramine or charcoal administration is recommended to

accelerate elimination. Studies with both hemodialysis and CAPD (chronic ambulatory

peritoneal dialysis) indicate that the primary metabolite of leflunomide, is not

dialyzable.

Mechanism of Action

Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate

dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has anti-

proliferative activity.

Pharmacokinetics

Following oral administration, leflunomide is metabolized to an active metabolite (A77

1726), Teriflunomide which is responsible for essentially all of its activity in-vivo.

Structure of Teriflunomide

Absorption

Following oral administration, peak levels of the active metabolite occurred between 6 -

12 hours after dosing.

Distribution

Teriflunomide has a low volume of distribution (Vss = 0.13 L/kg) and is extensively

bound (> 99.3%) to albumin in healthy subjects.

Metabolism

Leflunomide is metabolized to one primary and many minor metabolites.

Elimination

The active metabolite teriflunomide is eliminated by further metabolism and subsequent

renal excretion as well as by direct biliary excretion.

Washout period

Cholestyramine 8 g is administered 3 times daily and alternatively activated charcoal is

administered 4 times daily. The duration of complete washout is usually 11 days.

Special Populations

Gender: Gender has not shown to cause a consistent change in the in vivo

pharmacokinetics of teriflunomide.

Age: Age has been shown to cause a change in the in vivo pharmacokinetics of

teriflunomide.

Smoking: Smokers have a 38% increase in clearance over non-smokers; however, no

difference in clinical efficacy was seen between smokers and nonsmokers.

Hepatic insufficiency: The use of leflunomide in patients with hepatic insufficiency is

not recommended.

4.2. PLANT PROFILE- Cardiospermum halicacabum Linn.

Scientific Classification

Kingdom : Plantae

Order : Sapindales

Family : Sapindaceae

Subfamily : Sapindoideae

Genus : Cardiospermum

Species : halicacabum

Biological source : Cardiospermum halicacabum Linn.109-111

Synonym : Cardiospermum corundum, Cardiospermum glabrum,

Cardiospermum microcarpum, Cardiospermum microspermum,

Cardiospermum villosum.

Common Name : Balloon vine, heart pea, blister creeper, heartseed, winter cherry

Vernacular names :

Tamil : Mudukkottan, Modikkottan

Telugu : Vekkudutiga, Buddakakara

Hindi : Kanphuti, Kapalphoti

Malayalam : Ulinna, Paluruvan

Sanskrit : Sakralata, Jyotishmati

Kannada : Agniballe, Kakaralata

Fig. 4: Cardiospermum

halicacabum habitat

http://en.wikipedia.org/wiki/Plant

http://en.wikipedia.org/wiki/Sapindales

http://en.wikipedia.org/wiki/Sapindaceae

http://en.wikipedia.org/w/index.php?title=Sapindoideae&action=edit&redlink=1

http://en.wikipedia.org/wiki/Cardiospermum

Habitat

Cardiospermum halicacabum (Fig.: 4) is smaller, less woody and commonly annual

climber with tendrils, have large flat biternate leaves. Fruit consists of three dorsally

keeled membranous capsules each consisting of three internal blades. The fruit are

septifragal with the capsules breaking away from each other when fruit are ripe,

changing colour from green to brown.

Ethnomedicinal Uses

Roots are diuretic, diaphoretic, emetic, mucilaginous, laxative, emmenagogue. Also

useful in fever, arthritis, amenorrhoea, lumbago and neuropathy. Leaves are rubefacient

and are good for arthritis, otalgia and ophthalmodynia. Seeds are tonic, diaphoretic and

are used in arthritis and fever. The plant has sedative action on CNS. In view of

importance of the plant in the indigenous system of medicine and the importance of

modifications in the natural system of medicine for better patient compliance, many

studies have been carried out by several group of researchers.

4.3. EXCIPIENT PROFILE112

i) Lactose Monohydrate

1. Nonproprietary Names

BP : Anhydrous Lactose

JP : Anhydrous Lactose

PhEur : Lactose monohydricum, Anhydrous

USP-NF : Anhydrous Lactose

2. Functional Category

Binding agent, diluent for dry-powder inhalers, directly compressible tablet excipient,

dry powder inhaler carrier, lyophilization aid, tablet and capsule diluent, tablet and

capsule filler.

3. Applications in Pharmaceutical Formulation or Technology

Lactose is widely used as a filler or diluent in tablet capsules and inhalation products.

Direct-compression grades are often used to carry small quantities of drug and this

permits tablets to be made without granulating. Concentrations of lactose generally used

in these formulations are from 65% to 85%. Anhydrous lactose is widely used in direct

compression tablets. Anhydrous lactose can be used with moisture-sensitive drugs due

to its low moisture content. It may also be used in intravenous injections.

4. Description

Color : White to off-white

Nature : Crystalline / powdery

Odor : Odorless

Taste : Slightly Sweet

5. Typical Properties

Density (true) : 1.589 g/cm3

Density (bulk) : 0.71 g/cm3

Density (tapped) : 0.88 g/cm3

Solubility : Practically insoluble in Chloroform, Soluble in water, sparingly

soluble in ethanol (95%) and ether

6. Stability and Storage Conditions

Mold growth may occur under humid conditions (80% RH and above). Lactose may

develop a brown coloration on storage, the reaction being accelerated by warm, damp

conditions. Lactose anhydrous should be stored in a well-closed container in a cool, dry

place.

7. Incompatibilities

A Maillard-type condensation reaction is likely to occur between lactose and

compounds with a primary amine group to form brown or yellow-brown colored

products. Lactose is also incompatible with amino acids, aminophylline, amphetamines,

and Lisinopril. Lactose anhydrous is incompatible with strong oxidizers. When

mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or

lactose monohydrate when stored for six weeks at 40°C and 75% RH, the mixture

containing anhydrous lactose showed greater moisture uptake and drug degradation.

8. Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of materials

handled. Excessive generation of dust or inhalation of dust should be avoided.

9. Regulatory Status

Generally Recognized as Safe (GRAS) listed. Included in the FDA Inactive Ingredients

Database

10. Related Substances

Lactose inhalation, lactose monohydrate, lactose spray-dried.

ii) STARCH


BP : Maize starch, Potato starch, Rice Starch, Tapioca Starch, Wheat Starch.

JP : Corn Starch, Potato Starch, Rice Starch, Wheat Starch.

PhEur : Maize Starch, Pea Starch, Potato Starch, Rice Starch, Wheat Starch.

USP-NF : Corn Starch, Potato Starch, Tapioca Starch, Wheat Starch.


Glidant, tablet and capsule diluents, tablet and capsule disintegrant, tablet binder,

thickening agent.

3. Applications in Pharmaceutical Formulation or Technology

Binder : 5-25%

Disintegrant : 3-15%

Starch is also used in dry-filled capsule formulations for volume adjustment of the fill

matrix and to improve powder flow especially when using dried starches. Starch

quantities of 3–10% w/w can act as an anti-adherent and lubricant in tableting and

capsule filling. Starch is one of the most commonly used tablet disintegrants at

concentration of 3–25% w/w, a typical concentration is 15%.

4. Description

Color : White

Nature : Fine, comprising very small spherical or avoid granules

Odor : Odorless

Taste : Tasteless


pH in the range : 4.0–8.0




Flowability : 30% Carr’s index

Solubility : Practically insoluble in cold ethanol (96%) and in cold water.

Starch swells instantaneously in water by about 5–10% at 37°C.

Starch becomes soluble in hot water at temperatures above the

gelatinization temperature. Starches are partially soluble in

dimethyl sulfoxide and dimethyl formamide.

6. Stability and storage conditions

Dry starch is stable if protected from high humidity. Starch is considered to be

chemically and microbiologically inert under normal storage conditions. Starch

solutions or pastes are physically unstable and are readily metabolized by

microorganisms; they should therefore be freshly prepared when used for wet

granulation. Starch should be stored in an airtight container in a cool, dry place.


Starch is incompatible with strongly oxidizing substances. Colored inclusion

compounds are formed with iodine.

8. Handling precautions

Observe normal precautions appropriate to the circumstances and quantity of material

handled. Eye protection and a dust mask are recommended. Excessive dust generation

should be avoided to minimize the risks of explosion

9. Regulatory status

GRAS listed. Included in the FDA Inactive Ingredients Database

10. Related substances

Dextrin, hydroxypropyl starch, maltodextrin, sodium starch glycolate, starch

pregelatinized.

iii) MAGNESIUM STEARATE


BP : Magnesium Stearate

JP : Magnesium Stearate

PhEur : Magnesium Stearate

USP-NF : Magnesium Stearate

2. Functional Categories

USP : Tablet and capsule lubricant.

BP/EP : Lubricant, pharmaceutical aid.

Others : Glidant, Anti adherent.

3. Applications in pharmaceutical formulation or technology

Magnesium stearate is widely used in cosmetics, food and pharmaceutical formulations.

It is primarily used as a lubricant in capsule and tablet manufacture at concentrations

between 0.25% and 5.0% w/w. It is also used in barrier creams.

4. Description

Color : White

Nature : Fine, precipitated or milled, impalpable powder

Odor : Slight characteristic

Taste : Slight characteristic





Flowability : Poorly flowing, cohesive powder.

Solubility : Practically insoluble in ethanol, ethanol (95%), ether and water;

slightly soluble in warm benzene and warm ethanol (95%).


Magnesium stearate is stable and should be stored in a well-closed container in a cool,

dry place.


Incompatible with strong acids, alkalis and iron salts. Avoid mixing with strong

oxidizing materials. Magnesium stearate cannot be used in products containing aspirin,

some vitamins and most alkaloidal salts.



handled. Eye protection and gloves are recommended. Excessive inhalation of

magnesium stearate dust may cause upper respiratory tract discomfort, coughing and

choking. Magnesium stearate should be handled in a well-ventilated environment, a

respirator is recommended.

9. Regulatory Acceptances

GRAS listed. Accepted as a food additive in the USA and UK. Included in the FDA

Inactive Ingredients Database

10. Related Substances

Calcium stearate, magnesium aluminum silicate, stearic acid, zinc stearate.

iv) AEROSIL


BP : Colloidal Anhydrous Silica

JP : Light Anhydrous Silicic Acid

PhEur : Silica, Colloidal Anhydrous

USP-NF : Colloidal Silicon Dioxide


Adsorbent, anti-caking agent, emulsion stabilizer, glidant, suspending agent, tablet

disintegrant, thermal stabilizer, viscosity-increasing agent.

3. Applications in pharmaceutical formulation or technology

Colloidal silicon dioxide is widely used in pharmaceuticals, cosmetics and food

products. Its small particle size and large specific surface area give it desirable flow

characteristics that are exploited to improve the flow properties of dry powders in a

number of processes such as tableting and capsule filling.

Uses of colloidal silicon dioxide Use Concentration (%)

Aerosols : 0.5–2.0

Emulsion stabilizer : 1.0–5.0

Glidant : 0.1–1.0

Suspending and thickening agent : 2.0–10.0

4. Description

Colloidal silicon dioxide is submicroscopic fumed silica with a particle size of about 15

nm.

Color : Bluish-white

Nature : Light, loose, non gritty amorphous powder

Odor : Odorless

Taste : Tasteless


Density (bulk) : 0.029–0.042 g/cm3

Density (tapped) : 0.042 – 0.069 g/cm3

Flowability : 35.52% Carr’s index

Solubility : Practically insoluble in organic solvents, water and acids,

except hydrofluoric acid, soluble in hot solutions of alkali

hydroxide. Forms a colloidal dispersion with water.


Colloidal silicon dioxide is hygroscopic but adsorbs large quantities of water without

liquefying. Colloidal silicon dioxide powder should be stored in a well-closed

container.


Incompatible with diethylstilbestrol preparations



handled. Eye protection and gloves are recommended. Considered a nuisance dust,

precautions should be taken to avoid inhalation of colloidal silicon dioxide. In the

absence of suitable containment facilities, a dust mask should be worn when handling

small quantities of material. For larger quantities, a dust respirator is recommended.

Inhalation of colloidal silicon dioxide dust may cause irritation to the respiratory tract

but it is not associated with fibrosis of the lungs (silicosis), which can occur upon

exposure to crystalline silica.

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14. chapter iv- review of drug, plant & excipients.pdf