Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
31
Dosage Form Design: Pharmaceutical and Formulation Considerations
2
The Need for dosage forms
To protect the drug substance from the atmospheric oxygen or humidity (coated tablets, sealed ampuls)
To protect the drug substance from gastric acid after oral administration (enteric-coated tablets)
To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets, flavoured syrups)
To provide liquid preparations of drug substances, either as dispersions (suspensions) or as clear preparations (solutions)
To provide rate-controlled drug action(various controlled-release tablets, capsules, and suspensions)
3
The Need for dosage forms
To provide optimal drug action from topical administration sites (ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations)
To provide for insertion of a drug into one of the body’s orifices (rectal or vaginal suppositories)
To provide for placement of drugs directly in the bloodstream or body tissues (injections) To provide for optimal drug action through inhalation therapy (inhalants and inhalation aerosols)
4
General Considerations in dosage form design
systemic use …..oral administration
emergency …..injectable form
nausea, and vomiting…..skin patches, suppositories, injections. infants and children younger than 5 years of age…..solutions, syrups, or suspensions
childhood and even adulthood…..flavored chewable tablet, capsules
5
Pre-formulation studies
Physical Description 1- solid: stability, small, accurately dosed, tasteless,70% of the time by community pharmacists
2- liquidProblems:volatile and must be physically Hard to formulate in tablet Solution:sealed from the atmosphere to prevent evaporation loss nitroglycerin Incapsulate in soft capsules Vitamins A, D, and E
6
Pre-formulation studies
Microscopic Examination Spherical and oval powders flow more easily than needle-shaped powders and make processing easier.
Heat of Vaporisation The amount of heat absorbed when 1 g of a liquid vaporises is known as the heat of vaporisation of that liquid and is measured in calories. aerosol dosage.
The smaller the particle size, the greater the vapour pressure. This demonstrates the importance of personnel protection.
7
Pre-formulation studies
Melting Point Depression determine the purity of a drug substance, the compatibility of various substances before inclusion in the same dosage form.
The temperature at which the pure liquid and solid exist in equilibrium.
eutectic point
8
Pre-formulation studies
Particle Size Affect dissolution rate, bioavailability, content uniformity, taste, texture, colour, and stability, flow characteristics, sedimentation rates, absorption.
Polymorphism crystal or amorphous form of the drug substance. Polymorphic forms usually exhibit different physicochemical properties, including melting point and solubility. At least one third of all organic compounds exhibit polymorphism.
The energy required for a molecule of drug to escape from a crystal is much greater than is required to escape from an amorphous powder. Therefore, the amorphous form of a compound is always more soluble than a corresponding crystal form.
9
Solubility For a drug to enter the systemic circulation and exert a therapeutic effect, it must first be in solution.
Pre-formulation studies
solubility test: an excess of the drug is placed in a solvent and shaken at a constant temperature over a long period until equilibrium is obtained, then the drug will be analysis.
10
Pre-formulation studies
Solubility and Particle Size small increases in solubility can be accomplished by particle size reduction Solubility and pH Weak acidic or basic drugs may require extremes in pH that are outside accepted physiologic limits or that may cause stability problems with formulation ingredients.
11
Pre-formulation studies
Dissolution Sedimentation in gastric fluid, it will do so in the form of fine particles with a large surface area. dissolution rate: the time it takes for the drug to dissolve in the fluids at the absorption site, is the rate limiting step in absorption.
The value is expressed as milligrams dissolved per minute per square centimetre.
Ficks first law
Noyes and Whitney law
12
Pre-formulation studies
Membrane Permeability passage of drug molecules across biologic membranes
The biologic membrane acts as a lipid barrier to most drugs and permits the absorption of lipid- soluble substances by passive diffusion
Data obtained from the basic physicochemical studies, pKa, solubility, and dissolution rate, provide an indication of absorption.
13
Pre-formulation studies
Partition coefficient The oil–water partition coefficient is a measure of a molecule’s lipophilic character
14
Pre-formulation studies
Hydrates and Solvates
Hygroscopic powders are those that will tend to absorb moisture from the air.
Deliquescent powders are those that will absorb moisture from the air and even liquefy.
Efflorescent powders are those that may give up their water of crystallisation and may even become pasty.
15
Pre-formulation studies
Organic Salt considerations
Because many drugs are either weak acids or weak bases and have limited water solubility, they are often used as their “salts” to increase their aqueous solubility.
The dose depends on salt or base form.
16
Pre-formulation studies
Potency-Designated active Pharmaceutical ingredients
APIs have potencies based on “activity” or “micrograms per milligram” or other standard terms.
These are described for each API in the USP.
17
Pre-formulation studies
Complex Organic Molecules
Pharmacists involved in working with or handling biologically active proteins must be interested in their stabilisation, formulation, and delivery to the site of action.
18
Pre-formulation studies
Drug and Drug Product Stability
Stability studies conducted in the pre formulation phase include solid-state stability of the drug alone, solution-phase stability, and stability in the presence of expected excipients.
19
Pre-formulation studies
Drug Stability: Mechanisms of Degradation
Hydrolysis is a (drug) molecules interact with water molecules to yield breakdown products. For example, aspirin.
Hydrolysis is the most important single cause of drug decomposition. It affects esters or contain such other groupings as substituted amides, lactones, and lactams.
Oxidation destroys aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils. Oxidation is loss of hydrogen and involves free chemical radicals, which are molecules or atoms containing one or more unpaired electrons.
20
Pre-formulation studies
Drug and Drug Product Stability: Kinetics and Shelf life
Chemical Physical Microbiologic Therapeutic Toxicologic
21
Pre-formulation studies
Rate Reactions
Zero-Order Rate Reactions
First-Order Rate Reactions
22
Pre-formulation studies Enhancing Stability of Drug Products Buffers an aqueous solution, that can resist changes in pH upon addition of an acid or a base. Buffers are composed of a weak acid and its conjugate base or a weak base and its conjugate acid.
Antioxidants sulphites, light, chelating agents, opaque containers.
23
Group Activities
individual activities
24
Thalidomide
25
• Thalidomide was discovered by scientists at a German pharmaceutical company around 1953
• The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative
• Thalidomide was first marketed in 1957 in West Germany
• Thalidomide was primarily prescribed as a sedative or hypnotic
• Thalidomide also claimed to cure anxiety and insomnia
Thalidomide
26
• Thalidomide was also effective against nausea and to alleviate morning sickness in pregnant women.
• Thalidomide became an over-the-counter drug in West Germany on October 1, 1957. Shortly after the drug was sold in West Germany, between 5,000 and 7,000 infants were born with malformation of the limbs.
• Only 40% of these children survived
• The negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development
Thalidomide
27
• Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers
• The (R)-enantiomer has sedative effects
• The (S)-isomer causes malformation of the limbs (teratogenic)
• Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.
Thalidomide
28
29
30
31
Botulinum
32
41
https://bit.ly/2Hy1xee
2
https://bit.ly/2Hy1xee
3
MOCK TEST
4
QUESTION 1The initial human dose is usually ..…… of the highest non-toxic dose in animalsالجرعة ا-ولية ا<عطاة ل9نسان يجب أن تكون ……. -على جرعة غير سمية في
حيوانات التجارب
A. 10x (عشرة أضعاف)
B. 1/10
C. 1/100
D. 1/1000
5
QUESTION 2In phase 1 clinical trials, the human subjects are usually ……
في الطور ا-ول من اختبارات ا-دوية سريرياً، ا-شخاص اللذين يخضعون
للتجربة هم ……
A. Males volunteers (متطوعون ذكور)
B. Sick children (أطفال مرضى)
C. Maternal parents (الحوامل)
D. Healthy volunteers (متطوعون أصحاء)
6
QUESTION 3What is the maximum effective concentration in the figure below?
ما هو الحد ا-على للجرعة العbجية في الشكل أدناه
A. 4.0 mcg/ml
B. 2.0 mcg/ml
C. 4.0 hours
D. 8.0 hours
7
QUESTION 4The Lethal doe (LD50) of Botulinum is estimated to be ……… of body weight
الجرعة ا<ميتة الوسطية تقدر ب حوالي ….. من وزن الجسم
A. 2.0 ng/kg
B. 20 ng/kg
C. 5.0 ng/kg
D. 50 ng/kg
8
QUESTION 5A medicine is different than a drug because the medicine ..…
الدواء يختلف عن العقار -ن الدواء …..
A. is designed to give positive or negative effects مصمم jعطاء تأثيرات إيجابية أو سلبية
B. Is designed to give positive effect onlyمصمم jعطاء تأثيرات إيجابية فقط
C. contains only the active ingredient يحتوي على ا<ادة الدوائية الفعالة فقط
D. Does not have side effects r يترافق مع أعراض جانبية
9
In vomiting, the used dosage forms are:اrشكال الصيدrنية ا<ستخدمة في حاrت اrقياء
A. Skin patches (اللصاقات الجلدية)
B. Suppositories (التحاميل)
C. Inhalation (ستنشاقيةrشكال اrا)
D. A+C
QUESTION 6
10
Purity of API can be tested by:تفحص نقاوة ا-واد الدوائية عبر:
A. Microscope (الفحص ا<جهري)
B. Melting point (نصهارrفحص ا)
C. Solubility test (ليةbنحrفحص ا)
D. B+C
QUESTION 7
11
Particle size affects: يؤثر حجم ا;جزاء على:
A. Dissolution rate (معدل الذوبان)
B. Flow characteristics (خواص التدفق)
C. Absorption (متصاصrا)
D. All are correct (كل ما سبق)
QUESTION 8
12
Weak acidic drugs are soluble in:الحموض الضعيفة منحلة في:
A. pH=7
B. pH less than 7
C. pH more than 7
D. Oils (الزيوت)
QUESTION 9
13
During the formulation of proteins, pharmacist must be interested in اثناء صياغة البروتينات فإن الصيد;ني يجب ان يهتم ب:
A. Stabilisation (الثباتية)
B. Melting point (نصهارrنقطة ا)
C. delivery to the site of action (يصال <وقع التأثيرrا)
D. A+C
QUESTION 10
14
Pharmaceuticals ILecture 4
15
ADMEThe absorption, distribution, metabolism, and
elimination of a drug from the body are dynamic processes that continue from the time a drug is
taken
16
AbsorptionThe absorption, distribution, metabolism, and elimination of a drug from the body are dynamic processes that continue from the time a drug is taken
Blood
Not reversibleGastrointestinal tract
Skin
intramuscular
Not reversible
Not reversible
17
Absorption
What about intravenous injections?
18
Absorption
Blood
Not reversibleGastrointestinal tract
Skin
intramuscular
Not reversible
Not reversible
Intravenous injectionintravenous injection bypasses the absorption barrier
19
Distribution• The transfer of drug from the blood to other body locations (compartments)
is generally a rapid and reversible process
• The drug in the blood exists in equilibrium with the drug in the other compartments
Brain
Lungs
Muscles
Liver
Kidneys
Adipose
BloodReversible
Equilibrium
20
Distribution• The body locations to which a drug travels may be viewed as separate
compartments.
• Each compartment contains some fraction of the administered dose of drug
BloodReversible
Equilibrium
Brain
Lungs
Muscles
Liver
Kidneys
Adipose
21
Distribution
One compartment model
Blood Body CompartmentsReversible
Equilibrium
22
MetabolismDuring metabolism a drug substance may be metabolized into pharmacologically active or inactive metabolites, or both.
The metabolism of a drug to inactive products is an irreversible process that leads to the excretion of the drug from the body, usually via the urine
23
Prodrugs
24
ProdrugsProdrug is a term used to describe a compound that requires metabolic biotransformation (metabolism) after administration to produce the desired pharmacologically active compound
The conversion of an inactive prodrug to an active compound occurs primarily through enzymatic processes
25
Why Prodrugs?1. Solubility
A prodrug may be designed to possess solubility advantages over the active drug, enabling the use of specifically desired dosage forms and routes of administration.
2. Absorption
A drug may be made more water or lipid soluble, as desired, to facilitate absorption via the intended route of administration.
26
Why Prodrugs?3. Biostability
If an active drug is prematurely destroyed by biochemical or enzymatic processes, the design of a prodrug may protect the drug during its transport in the body
4. Prolonged Release
Depending on the prodrug’s rate of metabolic conversion, it may provide prolonged drug release and extended therapeutic activity.
27
ADME
• Gastrointestinal tract, intramuscular injection and subcutaneous injection are subjected to A D M E
• Intravenous Injection is only subjected to D M E
28
Principles of Drug Absorption
Before an administered drug can arrive at its site of action, it must cross a number of barriers.
EXAMPLE
• A drug taken by mouth must• Traverse the gastrointestinal membranes (stomach and intestines)• Gain entrance to the general circulation• Pass to the organ or tissue with which it has affinity• Gain entrance to that tissue• Enter its individual cells
29
Principles of Drug AbsorptionThe membranes in the body may be viewed in general as a lipid layer (fat containing).
Drugs are thought to penetrate these biologic membranes in two general ways:
1. Passive diffusion
2. Specialized transport mechanisms
30
Passive DiffusionPassive diffusion is the passage of drug molecules through a membrane that does not actively participate in the process.
The absorption process is driven by the concentration gradient across the membrane, with the passage of drug molecules occurring primarily from the side of high concentration
31
Passive DiffusionThe rate of diffusion of a drug across the membrane depends on:
1. The concentration gradient 2. The affinity for lipid and rejection of water (Hydrophobic)
Because of the lipid nature of the cell membrane, it is highly permeable to lipid-soluble substances.
The greater its affinity for lipid, the faster will be its rate of penetration into the lipid-rich membrane.
32
Passive DiffusionCells are also permeated by water and lipid-insoluble substances, it is thought that the membrane also contains water-filled pores or channels that permit the passage of these types of substances.
As water passes in bulk across a porous membrane, any dissolved solute with small enough molecules to traverse the pores passes in by filtration.
33
Passive DiffusionCell membranes are more permeable to the un-ionized forms of drugs than to their ionized forms, mainly because of the greater lipid solubility of the un-ionized forms and the highly charged nature of the cell membrane … higher surface area too
Ionized drugs unionized drugs
Water soluble Lipid soluble
34
Specialized transport Mechanisms
This type of transfer is for substances that are too lipid insoluble to dissolve in the lipid layer and too
large to flow or filter through the pores.
EXAMPLE Amino acids and glucose
35
Specialized transport MechanismsThis type of transport is thought to involve membrane components that may be enzymes capable of forming a complex with the drug at the surface membrane.
The complex moves across the membrane, where the drug is released, with the carrier returning to the original surface
36
Specialized transport MechanismsFeatures of specialized transport include:
1. Specialized transport may become saturated as the amount of carrier for a given substance becomes completely bound with that substance resulting in a delay in transport
2. Specialized transport include the specificity for a particular type of chemical structure, so that if two substances are transported by the same carrier, one will competitively inhibit the transport of the other
37
Specialized transport MechanismsThere are two types of specialized transport mechanism:
1. FACILITATED DIFFUSION A process where the solute or drug is moved across the membrane with a concentration gradient (it achieves the same concentration inside the cell as on the outside = equilibrium)
2. ACTIVE TRANSPORT A process where the solute or drug is moved across the membrane against a concentration gradient (from a solution of lower concentration to one of a higher concentration = no equilibrium)
38
Concentration vs time curve
39
Concentration vs time curveFollowing oral administration of a medication, if blood samples are drawn from the patient at specific time intervals and analyzed for drug content, the resulting data may be plotted on graph paper to yield the type of drug blood level curve presented below.
40
Concentration vs time curveThe y-axis: The vertical axis represents the concentration of drug in the blood (or serum or plasma)
The x-axis: The horizontal axis (x-axis) represents the time the samples were obtained following the administration of the drug
(Cmax) The peak height concentration
(Tmax) The time of the peak concentration
(AUC) The area under the blood concentration vs time curve
41
The Area Under The Curve (AUC)
The AUC is considered representative of the total amount of drug absorbed into the circulation following the administration of a single dose of that drug
42
The Area Under The Curve (AUC)Equivalent doses of a drug, when fully absorbed, produce the same AUC.
Thus, two curves dissimilar in terms of peak height and time of peak may be similar in terms of AUC and thus in the amount of drug absorbed
43
The Area Under The Curve (AUC)
The smaller the AUC, the lesser drug absorbed
OR
The bigger the AUC, the more drug absorbed
44
The Area Under The Curve (AUC)If equivalent doses of drug in different formulations produce different AUC values, differences exist in the extent of absorption between the formulations
45
Bioavailability
Bioavailability describes the rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action.
46
Bioavailability
Bioavailability is used to determine
1. The amount of drug absorbed from a formulation or dosage form
2. The rate at which the drug was absorbed
3. The duration of the drug’s presence in the biologic fluid or tissue
4. The relationship between drug blood levels and clinical efficacy and toxicity
47
Formulation A vs B
48
Still Alice
49
https://bit.ly/2DDuyUJ
50