preformulation_and_formulation(보충자료)

Report
PHARMACEUTICAL PREFORMULATION
AND FORMULATION
- Preformulation Investigations using Small Amounts of
Compound as an Aid to Candidate Drug Selection and
Early Development
Introduction: Decision gate system
Introduction: New drug R&D process
Introduction
•
Increasing in pressure on pharmaceutical companies to discover and develop new
medicines ever faster to replace those coming off patent and to counter generic
manufacturer competition.
• Since 1990 an average of only 28 drugs have been approved each year.
• Approved only 17 new chemical entities (NCEs) in 2002 (the lowest approvals).
• Success rate of bringing a candidate drug (CD) to market is no more than 10%.
• Out of 30,000 compounds synthesized only 0.003% of discovery compounds will
show a satisfactory return on investment.
 One idea to increase the productivity of the drug discovery process is
to eliminate those steps in the process that do not add value to the process chain.
•
Drug discovery process: lead generation (LG), lead optimization (LO)
• LG period: subdivided into the active to-hit(AtH) and the hit-to-lead (HtL) phases.
• HtL phase:
- utilizes high-throughput screening (HTS) and generates actives, hits, and leads.
- increases the drug-like properties (e.g., improve potency, selectivity,
pharmacokinetic properties, and decrease toxicity)
Introduction
• Leads: compounds that meet predefined chemical and biological criteria,
drug-like properties.
• LO phase (=prenomination)
- Structure-activity relationships (SARs), which correlate molecular properties
with biological effects, are derived.
- Iterative assessment of optimized leads --> identification of the most promising
lead candidates.
- 3~6 months
- Investigations for the physicochemical characterization of the solid and
solution properties of CD compounds.
- The aim of this phase: To provide an initial evaluation of compounds from a
development perspective and support the tolerability studies of compounds.
- During prenomination, compounds need to be evaluated in animals for
exposure/toxicity purposes [7-day tox and 28-day single and multiple ascending
doses].
Introduction
- During the prenomination phase, 50 to 100 mg compound is typically
available.
- A poor decision at this point  revisionary work  e.g., change of salt or
polymorph  delay to the development of the drug for the market
•
If the compound progresses into full development, a more complete
physicochemical characterization of the chosen compound should be carried out.
 Allowing a rational, stable, and bioavailable formulation to be progressed
through to launch.
•
The biggest change in the last decade.: Utilization of HTS technologies. 
Large number of compounds can be assessed for efficient physicochemical
profiling, as well as salt and polymorph screening.
Introduction
Introduction
Introduction
MOLECULAR PROPERTIES
Initial Physicochemical Characterization
•
Initial physicochemical characterization: 2-dimensional structural properties
• Performed by the discovery department.
• For example Nuclear magnetic resonance (NMR), mass spectra analysis, and
elemental analysis.
•
This text will focus on those tests carried out during prenomination that will
have an important bearing on the selection of a potential CD
pKa Determinations
•
Potential CDs that possess ionizable groups can be exploited to vary biological and
physical properties (e.g., binding to target enzyme or receptor, binding to plasma
proteins, gastrointestinal (GI) absorption, central nervous system (CNS) penetration,
solubility, and rate of dissolution).
• Therefore, one of the most important initial determinations carried out prior to their
development is the pKa or ionization constant(s).
• It is essential to know the extent to which the molecule is ionized at a certain pH,
because it affects the properties noted above.
• Brønstead and Lowry theory of acids and bases: An acid is a substance that can
donate a hydrogen ion, and a base is one that can accept a proton.
• For a weak acid, the following equilibrium holds:
• Henderson–Hasselbach equation relates the pKa to the pH of the solution and the
relative concentrations of the dissociated and undissociated parts of a weak acid
(equation 1).
pKa Determinations
•
•
Equation (2) to yield the percentage of a compound that will be ionized at any
particular pH.
Measurement of pKa
pKa Determinations
1) If a compound is poorly soluble in water  Measure the apparent pKa of the
compound in solvent-water mixtures, and then extrapolate the data back to a purely
aqueous medium (Methanol is by far the most popular).
2) If the compound contains an ultraviolet (UV) chromophore
 UV spectroscopy can be used.
 Mathematical analysis of the spectral shifts can then be used to determine the
pKa(s) of the compound.
3) pH indicator titration
 A novel approach
 The method works by calculating the pH from the indicator spectra in the visible
region and then obtaining the spectra in the UV
4) High-throughput pKa measurements
 The determinations were conducted in 96-well plates using 10-mM DMSO
solutions
 Determination of the pKa is via the change in UV absorbance at multiple
wavelengths as a function of pH.
pKa Determinations
 The Sirius ProfilerSGA (spectral gradient analysis) instrument:
- To deal with the ever-increasing numbers of compounds
- For high-throughput applications
- To overcome the low solubility exhibited by modern CDs, pKa measurements are
carried out in, for example, methanol-water mixtures.
- To overcome extreme solubility limitations of some compounds, a ternary
solvent system (methanol : dioxane : acetonitrile = 1:1:1) has been developed.
Prediction of pKa
•
The pKa may be estimated using a number of software packages, for example,
PALLAS, MARVIN, ACDpKa, and SPARC
The Partition and Distribution Coefficients
•
•
•
•
•
•
•
Many biological phenomena can be correlated with the partition coefficient (log P)
• Solubility, absorption potential, membrane permeability, plasma protein binding,
volume of distribution, and renal and hepatic clearance.
log P can be defined as the ratio of the concentration of the unionized compound, at
equilibrium, between organic and aqueous phases (equation 3).
log P = 0 means that the compound is equally soluble in water and the partitioning
solvent.
If the compound has a log P = 5, then the compound is 100,000 times more soluble
in the partitioning solvent.
log P values of less than 5 are best from a drug-like perspective.
log P values 1~ 3 show good absorption, greater than 6 or less than 3 often have
poor transport characteristics.
Highly lipophilic molecules reside in the lipophilic regions of membranes, and very
polar compounds show poor bioavailability because of their inability to penetrate
membrane barriers.
The Partition and Distribution Coefficients
•
Distribution coefficient (log D) takes into account the dissociation of weak acids and
bases. For a weak acid this is defined by equation (4).
•
combining this equation with equation (1) gives an expression relating the
distribution to the intrinsic lipophilicity (log P), the pKa of the molecule, and the pH
of the aqueous phase (equation 5).
Figure 1 shows the effect of ionization on the partitioning of a proton pump inhibitor
compound. This compound has a log P of 3.82 and three pKa values, that is, 1, 5.26,
and 8.63.
•
INITIAL SOLUBILITY
INVESTIGATIONS
INITIAL SOLUBILITY INVESTIGATIONS
•
•
•
The solubility of a CD may be the critical factor determining its usefulness since
aqueous solubility dictates the amount of compound that will dissolve and,
therefore, the amount available for absorption.
The importance of solubility, in biopharmaceutical terms, has been highlighted by its
use in the biopharmaceutics classification system (BCS).
High solubility is defined as the highest dose strength that is soluble in 250 mL.
Poorly soluble drugs: defined as an aqueous solubility of less than 100 mg/mL
•
From a physicochemical perspective, James (1986) has provided some general rules
regarding solubility:
1. Electrolytes dissolve in conducting solvents.
2. Solutes containing hydrogen capable of forming hydrogen bonds (H-bonds)
dissolve in solvents capable of accepting H-bonds and vice versa.
3. Solutes having significant dipole moments dissolve in solvents having
significant dipole moments.
4. Solutes with low or zero dipole moments dissolve in solvents with low or zero
dipole moments
INITIAL SOLUBILITY INVESTIGATIONS
•
The United States Pharmacopeia (USP) (Table 3) gives the following definitions of
solubility.
Phase Solubility Analysis
•
•
•
•
To more accurately determine the concentration of a saturated solution of a
compound, the following procedure can be used.
- A known volume of the solvent, water or buffer, is pipetted into a vial.
- The compound of interest is added until saturation is observed to occur.
- If the compound dissolves, then more compound is added and the experiment
restarted.
For HTS of solubilities, 96-well microtiter technique with an integral nephelometer
could be used.
Because of the differences in melting point and other characteristics of polymorphs,
solubility differences are often observed. Usually the most stable form of the
compound has the lowest solubility in any solvent.
Many CDs are ionizable organic compounds, and thus there are a number of
parameters that will determine the solubility of a compound,
for example, molecular size and substituent groups on the molecule, degree of
ionization, ionic strength, salt form, temperature, crystal properties, and
complexation.
Phase Solubility Analysis
•
•
•
•
To more accurately determine the concentration of a saturated solution of a
compound, the following procedure can be used.
- A known volume of the solvent, water or buffer, is pipetted into a vial.
- The compound of interest is added until saturation is observed to occur.
- If the compound dissolves, then more compound is added and the experiment
restarted.
For HTS of solubilities, 96-well microtiter technique with an integral nephelometer
could be used.
Because of the differences in melting point and other characteristics of polymorphs,
solubility differences are often observed. Usually the most stable form of the
compound has the lowest solubility in any solvent.
Many CDs are ionizable organic compounds, and thus there are a number of
parameters that will determine the solubility of a compound,
for example, molecular size and substituent groups on the molecule, degree of
ionization, ionic strength, salt form, temperature, crystal properties, and
complexation.
Effect of Molecular Size on Solubility
•
Because of interactions between the nonpolar groups and water, Large organic
molecules have a smaller aqueous solubility than smaller molecules.
•
It is dependent on the number of solvent molecules that can pack around the solute
molecule.
•
Figure 2 shows the effect of molecular weight on the solubility of some amino acids
in water.
INITIAL STABILITY
INVESTIGATIONS
INITIAL STABILITY INVESTIGATIONS
•
Knowledge about the chemical and physical stability of a CD in the solid and liquid
state is extremely important in drug development.
•
In the longer term, the stability of the formulation will dictate the shelf life of the
marketed product.
•
ICH spec.: The allowable levels of a single impurity permissible without toxicological
cover is much less than 1%.
•
To elucidate their stability with respect to, for example, temperature, pH, light, and
oxygen, a number of experiments need to be performed.
•
The major objectives of preformulation team are therefore to (1) identify conditions
to which the compound is sensitive and (2) identify degradation profiles under these
conditions.
•
The main routes of drug degradation in solution are via hydrolysis, oxidation, or
photochemical means.
Solution Stability
Hydrolysis
•
•
•
•
•
•
•
Degradation by hydrolysis is affected by a number of factors, of which solution pH,
buffer salts, and ionic strength are the most important.
In addition, the presence of cosolvents, complexing agents, and surfactants can also
affect this type of degradation.
As noted, solution pH is one of major determinants of the stability of a compound.
Hydroxyl ions are stronger nucleophiles than water, thus degradation reactions are
usually faster in alkaline solutions than in water, that is, OH– ions catalyze the
reaction.
In solutions of low pH, H+ can also catalyze hydrolysis reactions.
Buffer ions such as acetate or citrate can catalyze degradation.
Table 5 shows some examples of the functional groups that undergo hydrolysis.
Solution Stability
•
Therefore, although it is prudent to adjust the pH to the desired value to optimize
stability, this should always be done with the minimum concentration necessary.
Oxidation
•
The second most common way a compound can decompose in solution is via
oxidation.
•
Reduction/oxidation (redox) reactions involve one of the following processes:
(1) transfer of oxygen or hydrogen atoms or
(2) transfer of electrons.
•
Oxidation is promoted by the presence of oxygen, and the reaction can be initiated
by the action of heat, light, or trace metal ions that produce organic free radicals.
THE ORGANIC SOLID STATE
THE ORGANIC SOLID STATE
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Molecular solids can exist as crystalline or noncrystalline (amorphous) phases
depending on the extent of three-dimensional order and the relative
thermodynamic stability hierarchy.
Crystalline states can be described as a periodic array of molecules within a threedimensional framework.
Noncrystalline materials lack significant three-dimensional order, but may exhibit
lower-dimensional short-range order.
“Crystal proper” is defined as one in which the molecule is repeated to 10,000 to
100,000 times.
The structures of molecular crystals are influenced by both intramolecular and
intermolecular interactions.
Intramolecular forces determine molecular shape.
Intermolecular forces are relatively weak, their effect is largely short range.
 diversity in the arrangement of molecules within the molecular crystals is brought
about, which also gives rise to differences in properties and performance of the
molecular crystals.
Crystalline States and Structural Assessment
Polymorphism and Related Phenomena
•
Polymorphism is a solid-state phenomenon where the crystal structures of a
chemical entity are different, but correspond to identical liquid and vapor states.
•
A variation in crystal structure is brought about by differences in molecular packing
and intermolecular interactions within the three-dimensional framework of the
crystalline state.
•
Polymorphs will have different lattice energies, which in turn govern the physical
properties and behaviors of the material.
•
•
Specifically, in the area of pharmaceutical material selection, polymorphs are
selected on the basis of physical and chemical stability, behavior to processing and
formulation, and biopharmaceutical properties as an assessment of in vivo
performance.
Other differences in properties also include thermodynamic and kinetic variations
between polymorphs.
Crystalline States and Structural Assessment
Polymorphism and Related Phenomena
•
•
In addition to simple variations in hydrogen bonding, polymorphism can also be
induced by conformational differences, that is, the existence of different conformers
of the same molecule in different polymorphic modifications.  different solubility
properties.
Conformational polymorphism
 different solubility properties
 diversity in bulk properties: e.g., polychromism, different color, red, yellow, and
orange
 directly due to a variation in the molecular conformation, giving rise to
different three-dimensional packing
Polymorph Production Methods
•
Both solvent-mediated and nonsolvent-induced polymorphism can be employed.
1. Crystallization from different solvents under variable conditions, for example,
different agitation speeds and temperatures.
2. Precipitation by, for example, addition of an antisolvent to a solution containing the
drug or by pH adjustment of solutions of weak acids or bases.
(e.g., quasi-emulsion precipitation of a number of polymorphic compounds using
PEG300 as the solvent and water as the antisolvent.
3. Concentration or evaporation.
4. Formation of polymorphs from solvate desolvation. E.g., forms I of spironolactone
could be obtained by desolvation of its ethanol solvate.
Polymorph Production Methods
5. Crystallization from the melt, assuming that melting is not accompanied by thermal
degradation.
6. Grinding and compression.
7. Lyophilization (freeze-drying)
8. Spray-drying. Amorphous ursodeoxycholic acid can be prepared by spray-drying.
9. Crystallization from supercritical fluids.
10. Potentiometric cycling.
11. High pressure.
12. Sublimation. Exploiting the vapor phase as a solvent-free method
Case study:
The Items for DGS
(Decision gate system)
Preformulation, formulation study in R&D stage
Test Items
Stage
Physicochemical characterization
연구/전임상단계
Salt selection
연구/전임상단계
pH-Solubility
연구/전임상단계
pH-Stability
연구/전임상단계
Solid stability (Stability test)
연구/전임상단계
Hygroscopicity
전임상단계
Intrinsic dissolution rate (IDR)
전임상단계
Structure determination (XRD)
전임상단계
Preclinical formulation
전임상단계
Particle size analysis
전임상/임상단계
Excipient compatibility
전임상/임상단계
Polymorphism study
전임상/임상단계
Phase I formulation (Formulated capsule)
임상단계
Clinical formulation (Tablet or capsule)
임상단계
Remarks
Principal areas of preformulation research
Ⅰ. Bulk Characterization
Crystallinity and Polymorphism
Hygroscopicity
Fine Particle Characterization
Bulk Density
Powder Flow Properties
Ⅱ. Solubility Analysis
Ionization Constant-pKa
pH Solubility Profile
Thermal Effects
Solubilization
Partition Coefficient
Dissolution
Ⅲ. Stability Analysis
Stability in Toxicology Formulations
Solution Stability
pH Rate Profile
Solid State Stability
Bulk Stability
Compatibility
Preformulation research - Lead optimization stage
Physicochemical Characterization
시험구분
중요성
연구단계 & 전임상 단계 시험 항목
필요시료량
100mg
소요기간
1주
- Lead 화합물이나 전임상후보 화합물의 물리화학적 특성을 1차적으로 측정함.
- 물리적 특성에 따라 salt 또는 polymorph의 개발 여부를 판단하며, lead 최적화
단계에서는 구조 변형의 여부 판단에 관여됨.
시험방법
- 구조분석: NMR, IR, UV/VIS, MASS, XRD
- 열분석: DSC, TGA-MASS, HSM
- pKa, LogP/LogD
Criteria
- Log P가 > 5 용해도가 낮아 개발이 어려움  Salt화 가능성 판단
- Log P가 < 0 흡수가 어려움  Prodrug 가능성 판단
용어설명
- XRD (X-ray diffraction): X-선을 이용한 결정 격자 회절 방법, 결정의 구조를 조사
- DSC (Differential scanning calorimetry): API의 온도변화에 따른 열량 변화를 관찰,
일반적으로 화합물의 Melting temperature를 결정하는 데 사용
- TGA (Thermogravimetric analysis)-MASS: API의 온도에 따른 질량변화를 관찰.
주로 hydrate나 solvate 생성 여부를 관찰
- HSM: Hot-stage microscopy 온도 변화에 따른 결정의 변화를 현미경으로 관찰
Salt Selection
시험구분
중요성
연구단계 & 전임상 단계 시험 항목
필요시료량
300mg
소요기간
2~4 개월
- 전임상 후보에 대한 적합한 salt형을 선정함
- 난용성 API인 경우 salt를 만들어 solubility를 증대시킴
- Free form이 비정질이어서 안정성이 떨어지는 경우 salt로 만들어 stability를
증대시킴.
- 흡습성이 큰 API의 경우 적절한 salt 형으로 만들어 문제를 제거함
시험방법
- API에 basic 한 작용기 (주로 amine)가 있는 경우 acid를 반응시켜 물에 잘 녹는
salt를 만듦.
- Salt의 용해도와 생성여부를 판단하기 위해 먼저 in situ salt screening을 실시함.
Criteria
- Solubility
- Stability
- Crystallinity (Crystal Shape)
용어설명
- 비정질 (amorphous): 결정성 (crystallinity)이 없거나 매우 작은 solid form으로
일반적으로는 solubility가 증가하지만 stability는 떨어짐.
pH-Solubility
시험구분
중요성
연구단계 & 전임상 단계 시험 항목
필요시료량
100mg
소요기간
1주
- API의 수용액상 Solubility는 약물의 생체 흡수와 관련이 있어 약물의 유용성 면에서
매우 중요함.
- 각 장기 마다 pH가 다르기 때문에 pH에 따른 화합물의 solubility는 궁극적으로 약물
흡수와 관련이 있음.
시험방법
- 여러 다른 pH 완충수용액을 만들어 일정량의 API를 넣어 37℃로 유지시킨 다음
수용액상 API의 농도를 HPLC를 이용하여 분석함.
Criteria
- 주사제: 30mg/mL이상이면 이상적, 투여 용량에 따라 달라짐
- 경구제: Dose/250mL 이상이면 이상적
(예, 250mg을 투여해야 하는 경우 >1mg/mL)
용어설명
pH-Stability
시험구분
중요성
연구단계 & 전임상 단계 시험 항목
필요시료량
100mg
소요기간
1주
- API의 수용액상 Stability는 약물의 흡수 전후의 degradation이나 chemical
conversion*등을 관찰하거나 예견하는데 유용함.
- API가 가장 stable한 pH조건을 찾아내어 solution 상태의 formulation 개발에
활용할 수 있음 ( 동물실험 제형 및 사람에서의 solution 제형에 이용 가능)
시험방법
- 여러 다른 pH 완충수용액을 만들어 일정량의 API를 넣어 37 ℃ 로 유지시킨 다음
수용액상 API의 농도를 HPLC를 이용하여 분석함.
Criteria
- 24시간 경과 후에도 95% 이상 유지
용어설명
- Chemical conversion: 효소의 관여 없이 이화학적인 조건에서 화합물의
configuration이 변화하는 것 (Cis-trans conversion)
Solid Stability
시험구분
중요성
연구단계 & 전임상 단계 시험 항목
필요시료량
100mg
소요기간
4주
- API의 열에 대한 stability를 조사함.
- 빠른 판단을 위하여 stressed condition (60 ℃ )에서 4주간 stability를 조사함.
- 개발후보로 선정된 경우는 ICH guideline에 따라 분석팀에서 실시함.
시험방법
- 시료를 60℃ 항온 chamber에 보관하며, 1주일 간격으로 sampling하여 HPLC로
남아있는 시료량의 순도*를 분석함.
Criteria
- 가혹조건 (60 ℃)에서 3주 경과 후 95% 이상, 4주 경과 후 90% 이상 순도가 유지되는
경우 stable
용어설명
- 순도 (Purity): 일반적으로 순도는 HPLC를 이용하여 main peak의 % peak area를
계산하여 결정함.
Preformulation/Formulation research - Preclinical stage
Hygroscopicity
시험구분
중요성
전임상 단계 시험 항목
필요시료량
500mg
소요기간
2주
- API는 흡습성 정도에 따라 본래의 결정형을 유지하는 조건 및 시간이 정해짐.
- Highly hygroscopic 하거나 moderately hygroscopic 한 경우 moisture를
효과적으로 막을 수 있는 방법을 반드시 모색하여야 함.
시험방법
- API를 각각 상대습도가 다르게 정해진 용기에 넣고 용기 들을 온도가 조절되는 항온
장치에 보관하여 수일 간격으로 보관된 API의 무게 변화를 측정함.
- 무게 변화는 API에 수분의 변화를 설명하여, 이 경우 가시적으로 수분에 의한 API의
용해를 관찰할 수 있음.
Criteria
- Hydrate 형성 유무, non-or slightly hygroscopic
용어설명
- Hydrate: 화합물에 물이 일정한 비율로 포함되어 있는 것.
Intrinsic Dissolution Rate (IDR)
시험구분
중요성
전임상 단계 시험 항목
필요시료량
100mg
소요기간
2일
- API가 수용액에서의 용출되는 속도를 나타냄.
- 결정형 (polymorph)이나 salt의 종류에 따라서도 다르며, 약물의 제형화에
직접적으로 관련됨.
- IDR 결과를 비교하여 우수한 결정형이나 salt를 선정함.
시험방법
- API로 원형의 pellet을 만들어 pH에 따른 용출 속도를 측정함.
Criteria
- pH에 따른 용출속도 (기울기가 클수록 용출이 좋음). 여러 API의 비교 시 rate로 비교.
- 경구 제형의 dissolution과 연관하여 pH1.2에서 1시간 이내에 90%이상 용출되는
것이 바람직함.
용어설명
Structure Determination (XRD)
시험구분
중요성
전임상 단계 시험 항목
필요시료량
1g
소요기간
1~2 개월
- API의 결정구조 결정에 의해 개발 물질의 분자구조를 검증하고 final form을 확정함.
시험방법
- API를 여러 가지 결정화 조건에 따라 적당한 크기의 단결정을 키운다.
- 단결정을 이용하여 single-crystal diffractometer에서 격자회절을 측정한 다음
software를 이용, 결정구조를 결정하고 정밀화함.
Criteria
- R1 value 10% 이하 (%는 실측된 구조와 모델 구조와의 차이로 작은 수치가 좋다.)
- R2 value 30% 이하 (R1과 R2는 구조 정밀화 후 자동으로 산출됨)
용어설명
Preclinical Formulation
시험구분
중요성
전임상 단계 시험 항목
필요시료량
20~30mg
소요기간
2주
- 전임상 시험에서는 주로 solution formulation을 이용하는데, API를 필요한 농도에서
clear하게 녹일 수 있는 vehicle을 찾아내어 PK, Pre-toxicology, Toxicology study
등에 사용하고자 함.
시험방법
- API를 필요한 농도에서 clear하게 녹이는 최적의 formulation을 찾아냄.
- Formulation은 동물에 적용 가능한 vehicle을 사용해야 하며, 해당 formulation에
대한 formulation stability를 1~2주간 측정한 후 확정함.
Criteria
- 원하는 용해도와 stability를 만족하는 경우
용어설명
Particle Size Analysis
시험구분
중요성
전임상 단계 & 임상 단계 시험 항목
필요시료량
200mg
소요기간
1주
- Particle size에 따라 Tablet의 성형 정도 또는 Capsule에 충전 정도에 영향을 미치기
때문에 API의 Particle size는 약물의 제형화에 필수적 요소임.
시험방법
- API를 적당한 medium에 분산시켜 Light scattering particle size analyzer로 측정
- 또는 현미경 하에서 디지털 카메라로 찍어 software로 화면상의 particle size를
측정함.
Criteria
- Size (Uniformity), Shape (Uniformity, 선호도 Prismatic > Plate, Needle) 등 결과를
종합하여 Processability 판단에 반영.
- 제제시험 후 최적 particle size distribution 선정
용어설명
- Light scattering: laser 빛이 용액 내 particle에 부딪혀 scattering됨을 이용하여
particle의 size distribution을 측정함.
Excipient Compatibility
시험구분
전임상 단계 & 임상 단계 시험 항목
필요시료량
10~20g
소요기간
2~6개월
중요성
- 임상 개발후보의 제제화 시 Capsule이나 Tablet 제형에 들어갈 여러 가지 기능의
부형제 및 첨가제와 약물의 상호작용을 조사하여 compatible한 부형제 및 첨가제를
선정하고자 함.
시험방법
- API와 각각의 부형제를 1:1로 혼합하거나 여러 가지 부형제를 동시에 혼합하여
stressed condition (50 ℃ 또는 60 ℃ )에 보관한 후 1개월 간격으로 상호작용을
DSC/TGA, XRD와 HPLC등으로 분석을 하여, API와 가장 compatible한 excipient를
선정함.
Criteria
- 새로운 peak 생성여부 (50 ℃ 에 1개월 보관 후 새로운 peak를 생성하지 않거나 3개월
이내에 새로운 peak의 비율이 5% 이내의 excipient를 선정한다.
- 또는 60 ℃ 에 1개월 보관 후 새로운 peak를 생성하지 않거나 생성된 peak의 비율이
5%이내의 excipient를 선정한다.
용어설명
Polymorphism Study
시험구분
중요성
전임상 단계 & 임상 단계 시험 항목
필요시료량
50g
소요기간
6개월~1년
- API의 polymorph*를 조사하여 그 중 가장 적합한 것을 선정하여 final form으로
결정함.
- 전임상 단계에서 Salt인 경우와 아닌 경우에서 가능한 polymorph를 제조 및 물성
분석을 통하여 Final form으로 선정하고 개발 후보를 선정함.
시험방법
- API를 다양한 용매와 결정화 조건을 통하여 여러 가지 다른 결정형을 찾아냄.
- 각 결정형들의 Solubility, Stability, IDR* 등 물성을 비교
- 각 결정형들 사이에 변화 (transformation)가 있는지 조사
- 임상샘플 제조 시 polymorph의 생성 또는 변형을 조사
- 초기 screening에 50mg이 소요되며, polymorph가 발견되면 추가 실험에 50g 필요
Criteria
- Solubility, Stability, IDR
용어설명
- Polymorph: 동일한 화합물이 여러 가지 결정형을 가지는 경우 결정형에 따라 물리적
성질이 달라 약효도 달라질 수 있음.
- IDR (Intrinsic dissolution rate): 화합물이 수용액 용출되는 정도를 나타내는 수치
Bioavailability와 관련됨.
Phase I Formulation (Formulated Capsule)
시험구분
임상 단계 시험 항목
필요시료량
100g
소요기간
3~6개월
중요성
- 임상 1상 시험에 적합한 제형을 선정함.
- 체내에 투여되는 form이기 때문에 일반 의약품과 유사한 제형 형태로 만들어야 하며,
균일한 함량과 임상시험 실시 기간까지의 샘플의 stability 확보가 중요한 factor임.
시험방법
- 임상시험에 사용할 용량의 약물을 excipient compatible test에서 선정된 부형제와
혼합하여 capsule에 충전한 후, stability test를 진행하여 가장 적합한 formulation을
선정함.
Criteria
- 함량균일성, 용출, Stability
용어설명
- 함량균일성 (Content uniformity): 약물이 제형에 균일하게 잘 섞여있는 정도.
특히 약물 용량이 적은 경우 critical 함.
Clinical Formulation (Tablet or Capsule)
시험구분
중요성
임상 단계 시험 항목
필요시료량
1kg
소요기간
1~3년
- 임상 2,3 상 시험에 적합한 제형을 선정함.
- Clinical formulation은 약효시험 등 장기적인 시험에 이용되고 또 commercial
production의 기초가 되는 제형임.
시험방법
- API의 Excipient compatibility test를 통하여 선정된 부형제를 이용하여 적합한
크기의 Tablet이나 Capsule을 제조하여 함량균일성과 용출 및 Stability를 관찰하여
최적화된 제형을 선정함.
Criteria
- 함량균일성, 용출, Stability
용어설명

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