Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5875_Библиотеки_им_академика_М_И_Перельмана
.pdf
https://t.me/med1917
4
Handbook of 3D Printing in Pharmaceutics
proteomics, which are vital to predict diagnoses precisely and accurately, dene disease subtypes and suggest treatment. It is an advanced medical strategy with a higher
resolution towards understanding a disease condition to facilitate better targeting of
disease subtypes with newer therapeutic approach, for example, cystic brosis and
cancer (Strianese et al., 2020). 3DP operates on the principle of additive manufacturing (AM). It involves building up layers of material, one upon another, guided by
digital blueprints. Originally adopted in sectors like manufacturing and design prototyping, the technology has swiftly found its way into healthcare, where its precision
and adaptability are revolutionizing patient- specic interventions (Eshkalak et al.,
2020; Cox et al., 2016).
3DP has emerged as a promising tool in personalized medicine due to its ability
to create highly customized and patient- specic drug delivery systems, medical
devices, implants, and even tissues thus aid to greatly improve treatment outcomes
and patient experiences. Against the “one- size- ts- all” approach, which may not
always be optimal for every patient, 3DP allows for the design and development of
implantable systems and other medical devices to suit the individuals as per their
anatomy, precisely. This is particularly important in cases of complex surgeries or
implantations where the t and functionality of the device play a critical role in the
patient’s recovery and overall well- being (Pieters et al., 2022). The other applicative
aspect of 3DP towards personalized healthcare is in the area of surgery where 3DP
facilitates planning for surgical procedures, offering training and education for surgeons. Intricate surgical procedures may be planned by printing a replica as per the
anatomy of the patient. These models allow for better visualization of the patient’s
unique anatomy, which can help surgeons strategize and practice before the actual
procedure. This technology also aids in explaining procedures to patients, improving
their understanding and reducing anxiety (Ganguli et al., 2018; Calvo- Haro et al.,
2021). Cardiovascular healthcare benets from 3DP technology. Educationists may
utilize patient- specic 3D models to impart knowledge, explore the physiology and
functionality of valve and vessel function, plan for catheter- based surgical procedures,
design and rene the latest innovations in percutaneous structural devices (Vukicevic
et al., 2017)
3DP technology has aided diagnosis for over two decades where abstract medical data like computed tomography (CT) scans, magnetic resonance imaging (MRI)
images, and other diagnostic records could be transformed into tactile models,
allowing medical professionals to examine intricate details and anticipate potential
challenges. This immersive approach to preoperative planning expedites procedures,
minimizes complications, and ultimately enhances patient outcomes. By providing
surgeons with an accurate physical representation of a patient’s unique anatomy, 3DP
empowered them to navigate complex surgical landscapes with heightened condence (Rengier, 2010; Baylon et al., 2017). The versatility of 3DP extends to pro viding point- of- care manufacturing. In remote or underserved areas, 3DP could bring
medical solutions closer to patients. Point- of- care 3DP enables the on- site production
of medical devices, reducing the need for extensive supply chains and transportation (Point- of- Care 3D Solutions 3dsystems.com). Integrating 3DP technology into
hospitals led to production models, such as point- of- care manufacturing (Calvo- Haro
et al., 2021; Biglino et al., 2023).
https://t.me/med1917
Advancements in Tailoring Medication
5
Biofabrication is another prominent contribution of 3DP for personalizing
healthcare by printing biological materials to develop functional tissues and organs
that meet specic patient needs. This breakthrough could potentially alleviate the
organ shortage crisis and provide patients with life- changing treatments that were previously considered unattainable (Lewis, 2017). Biofabrication using a patient’s own
cells has the potential to transform the eld of transplantation by avoiding the necessity for organ donation as well as minimizing the possibility of its rejection, as the
printed tissues would closely match the patient (Agarwal et al., 2020). Biofabrication
in tissue engineering and regenerative medicine employs nanobiomaterials. In the
bioprinted model, cells will be seeded and grown. These biofabrication techniques
may be segregated as bioprinting and bioassembly. An example of biofabrication was
the use of polyether urethane- based nanostructured poly lactic glycolic acid (PLGA)
biolm for facilitating adhesion and proper functioning of the bladder smooth muscle
cells; use of silver nanoparticles in catheters for lowering the possibility of infection
(Di Marzio et al., 2020; Barazanchi et al., 2017).
1.2 ADVANCEMENTS IN 3DP OF PATIENT- SPECIFIC MEDICAL
DEVICES
Medical devices are therapeutic solutions to certain kinds of health issues, e.g.,
orthopedics. The variety of medical devices employed in healthcare is enormous. 3DP
sustained- release implants, stents, medical devices and contact lens nd use in joint
replacement treatment, medical prostheses, ophthalmic or cardiovascular indications.
3DP technology has facilitated the development and production of devices like
prosthetics, implants and scaffolds, which are designed to align as per the individual’s
body. As we look deeper into the intersections of 3DP and personalized medicine, it
becomes evident that this synergy has the potential to redene healthcare paradigms.
For hip and knee arthroplasty, traditionally, the surgeon would choose from a limited
range of implant sizes that might not perfectly t the patient’s anatomy resulting in
discomfort, reduced mobility, and the need for follow- up surgeries. 3DP obliterates
these limitations by enabling the creation of implants customized to the nest detail.
By translating a patient’s medical scans into digital designs and then physically fabricating implants layer by layer, 3DP ensures a precise t, enhancing not only the
implant’s functionality but also the patient’s overall quality of life (Kumar et al.,
2020). Prosthetics, such as limb replacements or orthopedic braces, can be designed
to t unique body shape and requirements of the patient. 3DP enables faster and more
cost- effective production of these devices, making them more accessible to a broader
range of patients.
Stents that are coated with scaffolds composed of biocompatible and biodegradable materials, and incorporate pharmaceuticals, have the potential to function as
drug delivery systems, particularly for antimicrobial agents. Recently, considerable
research was carried out on the development of customized patient- specic biocompatible scaffolds that are loaded with antimicrobials. These scaffolds are specically
designed to promote bone regeneration and prevent infections (Elsayed et al.,
2019). Surgical meshes were fabricated as interwoven structures, resulting in sheet-
like formations composed of biocompatible and sometimes biodegradable materials
https://t.me/med1917
6
Handbook of 3D Printing in Pharmaceutics
FIGURE 1.1 3D- printed medical devices for various healthcare applications (Jin et al., 2022).
of inorganic origin. Researchers are currently engaged in the development of novel
surgical meshes (Baylon et al., 2017). 3DP or AM techniques were employed to
produce implants composed of titanium that were capable of eluting antibiotics (Cox
et al., 2016). Selective laser- melting (SLM) technique was used to fabricate titanium
drug- delivery implants that facilitate drug release via micro- channels (Hassanin
et al., 2018). Drug- coated implants, scaffolds and meshes were manufactured utilizing AM technology in order to incorporate clinical functionality aimed at the prevention or treatment of infections, as well as the mitigation of pain (Mohanty et al.,
2015). Figure 1.1 presents some examples of 3D- printed medical devices in various
applications of healthcare (Jin et al., 2022).
1.3 DENTAL APPLICATIONS OF 3DP TECHNOLOGY FOR
PERSONALIZED THERAPY
Dentistry has beneted greatly from 3D printing. Dentists can produce highly
accurate crowns, bridges, and even entire sets of dentures tailored to each patient’s
oral structure. The digital scanning of a patient’s mouth combined with 3DP allows
for more comfortable and efcient dental procedures (Turkyilmaz and Wilkins, 2021).
Research in dentistry has undergone a signicant transformation with the advent of
3DP technologies. This transformation has been characterized by a shift towards
the production of dental prosthesis, articial teeth and shattered bone structures
that are constructed as per the requirement of the patient (Barazanchi et al., 2017;
Patel et al., 2017). AM is now being investigated as a potential method for producing
tissue scaffolds used in bone- graft surgeries. In the eld of periodontology,
3DP is employed for the production of patient- specic bio- absorbable ber- guided
scaffolds. These scaffolds are utilized for various purposes, such as sinus and bone
https://t.me/med1917
Advancements in Tailoring Medication
7
FIGURE 1.2 Crowns of upper jaw incisors produced by 3DP Technology (Schweiger
et al., 2021).
augmentation, socket preservation, as well as implant placement and maintenance in
cases of periodontal abnormalities (Gul et al., 2019). A guided tissue regeneration
membrane using platelet- rich brin for the treatment of severe bone deformities could
be developed by 3DP (Lei et al., 2019). Bio- resorbable scaffolds specically designed
for periodontal healing purposes were printed. PLGA was identied as a promising
polymer employed in scaffold creation in the context of guided bone regeneration
(Rasperini et al., 2015). Figure 1.2 shows one of the applications of 3DP in dentistry
where crowns of the teeth have been printed (Schweiger et al., 2021).
1.4 3D- PRINTED DRUG DELIVERY SYSTEMS FOR
INDIVIDUALIZED THERAPEUTIC APPROACHES
Personalized medicine often involves delivering drugs in specic dosages and
formulations tailored to an individual’s genetic makeup and health condition. 3DP
can create intricate drug delivery systems, such as pills with multiple compartments
releasing different medications at various rates, enhancing treatment efcacy and
reducing side effects (Mathew et al., 2020; Bacskay et al., 2022). Topical products
like dressings for wounds, micro- needle- based delivery systems, and medicated contact lens systems, were created by 3DP techniques. 3D nanoprinting for biologics
and nanotech- based drugs offers printed personalized nanomedicines in the years to
come. 3DP technology could be facilitated for continuous manufacturing via 3Dprinted microuidic chips and thus enable personalization to reach clinical practice
(Serrano et al., 2023). The delivery of drugs through the rectum or vagina has been
a longstanding practice, particularly suggested for youngsters, geriatrics, comatose patients, and those with difculty swallowing, to address a range of etiologies.
A recent study conducted research on the production of various patient- specic rectal
and vaginal rectal devices using AM. These devices were designed with diverse geometries and incorporated customized drug- eluting mechanisms (Fu et al., 2018). Fused
deposition modeling (FDM), stereolithography (SLA), binder jetting, powder- bed,
ink- jet printing (IJP) and semisolid extrusion are some 3DP/ AM methods employed
in pharmaceutical product development. Among such AM technologies, the powder
extrusion method led to successful formulation of amorphous solid printlets of
itraconazole, which overcame the lapses of FDM technology. AM has a possibility
https://t.me/med1917
8
for exible dosage form development by virtue of the exibility of materials selection
leading to personalized therapeutics (Katakam et al., 2022).
Handbook of 3D Printing in Pharmaceutics
Current studies are mostly centered on achieving high drug loading and developing
patient- specic treatments. Researchers are also exploring alternative drug delivery
systems, including buccal patches, transdermal patches, biodegradable implants
and oral- delivery systems. These alternative approaches are particularly valuable in
cases where conventional commercial methods are unable to offer the desired level
of pharmaceutical customization. One such advancement is in the development
AM technology for lipid- based drug delivery systems for lipophilic pharmaceutical
compounds (Vithani et al., 2018). The utilization of 3DP has several advantages,
particularly in terms of the exibility it provides in selecting materials. This attribute
enhances its applicability in the eld of multi- drug therapies. A poly- pill consisting of
four distinct cardiovascular medications was developed by 3DP (Pereira et al., 2019).
Similarly, 3D- printed mini- printlets incorporating paracetamol and ibuprofen as separate components were developed (Awad et al., 2019).
1.4.1 Oral DOsage FOrms
Oral solid dosage forms are widely recognized as the oldest and most well- established
pharmacological formulations due to their affordability, non- invasiveness, and
patient- friendly administration. There are various types of dosage forms available, including pills, tablets, capsules, lozenges, pellets, and lms. The xed- dose
combination therapy (FDCT) involves the administration of two medications in a
single tablet. This may not provide dosing exibility tailored to individual patients.
Secondly, the utilization of poly- therapy has the potential to exacerbate issues related
to drug adherence, hence leading to a subsequent decline in the overall health status
of patients. Thus the integration of many medications into a personalized formulation
tailored to individual patients suffering from chronic illnesses has the potential to
signicantly enhance treatment adherence and patient compliance. AM technologies
offer the capability to give numerous medications in a formulation with customized
shape, size, and desired drug- release patterns, hence circumventing the limitations of
conventional approaches (Norman et al., 2017; Alhnan et al., 2016; Angeliki et al.,
2020; Goyanes et al., 2019). The utilization of 3DP facilitates dosage form design
with customised geometry, design and shape. This capability has been challenging
to obtain through traditional manufacturing methods. 3DP methods have several
limitations, such as the production of porous materials and uneven shapes in dosage
forms (Pravin and Sudhir, 2018). To date, the utilization of FDM method is limited
to the printing of products exclusively for thermostable pharmaceuticals, employing
a restricted range of appropriate excipients. The utilization of SLA carries the risk
of drug degradation upon exposure to ultraviolet (UV) radiation, which serves as the
catalyst for the polymerization reaction (Prasad and Smyth, 2016). AM demonstrated
efcacy in developing sublingual, orodispersible, fast- disintegrating/ dissolving, and
immediate- release dosage forms (Jamróz et al., 2017; Musazzi et al., 2018; Kempin
et al., 2018; Solanki et al., 2018). Researchers have shown interest in exible thera peutic dosage forms that provide customized combinations of medicines, dosages and
desired release kinetics. For example, impact of varied tablet shapes on drug- release
https://t.me/med1917
Advancements in Tailoring Medication
9
kinetics, enabled the development of innovative dosage forms that possess specic
pharmacokinetic properties tailored to particular absorption locations within the
gastrointestinal tract (Goyanes et al., 2015).
1.4.2 Parenteral systems
Parenteral devices are utilized for the administration of medications through the intravenous (IV) route, employing either a catheter or a needle. The primary focus of previous research in the eld of intravenous (IV) devices pertained to the development
of personalized catheters designed for the targeted administration of pharmaceutical
agents. The production of catheters coated with drugs is being undertaken with the
aim of mitigating the occurrence of infections. The efcacy of antimicrobial coatings
in inhibiting bacterial adhesion to catheter surfaces has been demonstrated (Mathew
et al., 2019). In traditional coating procedures, the incorporation of an antimicrobial agent at a concentration of 2% w/ w was often employed to prevent bacterial
attack. However, the 3D- printed catheter tips exhibited antimicrobial properties at
lower concentrations of 1% w/ w, thereby demonstrating the technological superiority
of AM (Weisman et al., 2019). According to published statistics, the FDM technique
has emerged as a prominent method in the fabrication of catheters, showing potential
for future advancements (Weisman et al., 2015). The utilization of hot melt extrusion
(HME) is widely preferred in various applications due to its inherent benets, such as
the signicant reduction in organic solvent wastage and its environmentally sustainable characteristics (Keating et al., 2018). The capabilities of HME utilizing an FDM
printer for the development of modied drug- release systems composed of polymer
blends consisting of eudragits and polyvinly alcohol (PVA), along with the incorporation of polyethylene oxide (PEO), Polyethylene glycol (PEG), and Tween 80 were
investigated (Alhijjaj et al., 2016). A separate investigation was conducted wherein
wound dressings with patient- specic antibacterial metal ions were developed, demonstrating the potential of HME technology (Muwaffak et al., 2017). Successful
extrusion of laments composed of PEO, ethyl cellulose (EC), Eudragit RL100, and
PVA was performed. These laments were later utilized to produce discs through the
utilization of an FDM printer (Melocchi et al., 2016). The hot melt extrusion (HME)
technique can be utilized across a range of polymers in order to produce laments that
possess diverse physical characteristics, hence rendering them appropriate for various
medicinal applications (Tappa et al., 2018). A comprehensive examination of patient-
specic drug administration in relation to the design of 3D- printed dosage forms was
carried out highlighting many novel applications in this eld (Dumpa et al., 2021).
1.4.3 transDermal aPPlicatiOns
Transdermal patches are employed for the purpose of administering medications in a
systemic manner via the skin. The conventional manufacturing techniques employed
to produce a high rate of production are in direct competition with the need of tailoring
medication doses to individual patients (Adamo et al., 2016). In alternative terms,
the production of transdermal dosage forms can be expedited and uninterrupted,
hence accommodating individualized patient dosages concurrently. Transdermal
https://t.me/med1917
10
Handbook of 3D Printing in Pharmaceutics
FIGURE 1.3 Transdermal drug- delivery employing microneedle patches made by 3DP
(Villota et al., 2022).
thin- lm patches and micro- needles are employed for the systemic administration of
medications (Ita, 2015). Microneedle patches have emerged as promising
formulations for the transdermal delivery of medicines. The utilization of the SLA
microfabrication approach has been employed in the production of microneedle
patches with a notable level of precision, ranging from 1 to 25 m (Iliescu et al.,
2017). The process of selective laser sintering (SLS) necessitates multiple production
phases and the utilization of specialized equipment in order to produce miniature
items. Drug- coated and drug- eluting microneedles were manufactured by 3DP, which
presents numerous benets in comparison to traditional microfabrication approaches
(Caudil et al., 2018). Figure 1.3 is an image of 3D- printed microneedle patches
(Villota et al., 2022).
1.4.4 Films
3DP has been used to design and develop mucoadhesive, orodisperisble or ophthalmic
lms. Mucoadhesive lms are made using a variety of processes, including as hot-
melt extrusion, solvent casting, compression and 3D printing. Although the technique
most frequently employed in research is solvent casting (Elkanayati et al., 2022). The
developed 3D- printed orodispersible lms of aripiprazole by FDM, which works on
the basis of hot melt extrusion as a suitable method in the formation of lm with reproducible shape and drug content (Jamróz et al., 2017). Catechin loaded mucoadhesive
oral lm was 3D printed employing hydroxypropyl methylcellulose using the semi-
solid extrusion- type 3D printer. This study provides useful information on a model
pharmaceutical for personalized therapy (Tagami et al., 2019). The Hyrel 30M 3D
printer was used to create PLGA lms to evaluate drug- release behavior in vitro using
simulations and molecular models that elucidate drug– polymer interactions (Serris
et al., 2020). The mouth dissolving printed lm was produced by pneumatic- based
https://t.me/med1917
Advancements in Tailoring Medication
11
FIGURE 1.4 Photographic images of molded and 3D- printed suppositories containing 10%
(w/ w) paracetamol in the frontal view and internal view of partially printed suppositories.
From left to right: PEG mold, PEG “standard”, PEG “hollow”, PEG “small”, HF mold, HF
“standard”, HF “hollow”, HF “small” (Domsta et al., 2022).
microextrusion printing technology with ketorolac (a high potent low- dose and heat-
sensitive API) and was found feasible for highly exible small- scale printing, i.e.,
for personalized medicine (Khan et al., 2022). Levooxacin- loaded hydrogel- based
ophthalmic patches have been 3D printed to facilitate specied drug release in the eye
(Greymi et al., 2022).
1.4.5 suPPOsitOries
Drug administration via oral and IV routes is difcult in acute severe ulcerative colitis, which could lead to systemic adverse effects and limited dose availability at
the illness site. This would restrict the therapeutic effectiveness of the medication
(Hua et al., 2020). Oral medications intended for the colon have to pass through
the entire alimentary canal in order to reach the target site, which delays the therapeutic response (Awad et al., 2022; McCoubrey et al., 2023). A rectal formulation,
on the other hand, provides a substitute to improve therapeutic efcacy by optimizing
medication concentrations at the illness site and reducing systemic side effects (Hua
et al., 2019). Suppositories can also be self- administered by the patient unlike parenteral formulations. 3DP has facilitated development of suppository dosage forms.
Figure 1.4 shows 3DP paracetamol suppository employing PEG and hard fat (HF)
(Domsta et al., 2022).
Extensive work has been done on drug delivery systems employing 3DP, which
nd use in tailoring medication delivery for personalized treatment. Such reported
work has been compiled in Table 1.1.
1.5 CONCLUSION
The utilization of 3DP as an innovative technology across diverse domains in
healthcare favors the delivery of personalized treatment because it allows for the creation of patient- specic medical solutions. Such tailor- made interventions enhance
treatment outcomes, reduce complications, and improve overall patient satisfaction. The rst 3D- printed Spritam (Levitiracetam) tablet has paved the way for the
promising use of 3DP technology in developing drug delivery systems. Numerous
TABLE 1.1
https://t.me/med1917
Work Done on 3D- printed Drug Delivery Systems
S.No Drug Technology Formulation Excipients Parameters Studied
1. Paracetamol or caffeine
(Goyaneset al., 2016)
2. Budesonide (Goyanes et
al., 2015)
3. 4- aminosalicylic acid
(ASA) or 5- ASA
(Goyanes et al., 2015)
4. Hydrochlorothiazide
(Gioumouxouzis et al.,
2017)
5. Theophylline (Pietrzak et
al., 2015)
6. Prednisolone
(Skowyra et al., 2015)
7. Aripiprazole (Jamróz et
al., 2017)
FDM Caplets PVA lament (1.75 mm diameter, print
temperature 190– 220 °C) – USP grade
FDM Caplets PVA (1.75 mm diameter, print
temperature 190– 220 °C)
FDM Tablets PVA- (1.75 mm diameter, print
temperature 190– 220 °C)
FDM Tablets PLA lament (1.75 mm diameter, print
temperature 180– 220 °C, density 1.24
g/ mL)
FDM Tablets Eudragit RL100 and RS100
Hydroxypropyl cellulose (HPC) (SSL
grade) Triethyl citrate (TEC) and
triacetin
FDM Tablets PVA laments (melting point 160– 170
°C, specic heat 0.4 Cal/ g °C, density
1.25– 1.35 g/ cm3)
FDM Oral lms PVA (Poval 4– 88), Glycerol (85%),
Sodium Acetate Anhydrous, Hydranal®-
Water Standard 10.0
Porosity, dissolution test conditions
Drug loading of laments and
caplets, scanning electron
microscopy (SEM), x- ray powder
diffraction (XRPD)
thermal analysis, dynamic dissolution
Tablet morphology, strength,
friability, drug loading, dissolution
Drug loading in the lament
Drug content uniformity, drug-
release kinetics
Drug content, SEM
Drug content, thickness, mass, tensile
strength
disintegration time, F
modulus
, Young’s
max
12
Handbook of 3D Printing in Pharmaceutics
https://t.me/med1917
8. Methylene blue and
alizarin yellow (dyes)
(Prasad et al., 2016)
9. Paracetamol and alizarin
yellow (dye)
(Choi et al., 2009)
10. Pseudoephedrine
(Alhnan et al., 2016)
11. Chlorphenamine maleate
and uorescein (Ursan
et al., 2013)
12. Levetiracetam (Alhnan et
al., 2016)
13. Guaifenesin
(Ameeduzzafar et al.,
2018)
14. Nifedipine, glipizide,
and captopril
(Ameeduzzafar et al.,
2018)
15. Hydrochlorothiazide,
aspirin, pravastatin,
atenolol and Ramipril
(Patel et al., 2012)
16. Paracetamol (Jamróz et
al., 2018)
Binder jet
Tabular device Polycaprolactone (PCL), MCC and PEO Mechanical strength and durability,
printing
Binder jet
Tablets Kollicoat IR and Eudragit L100e55 Print resolution, drug content
printing
Binder jet
printing
Binder jet
printing
Cubic tabular
devices
Kollidon SR, hydroxyl propyl
methylcellulose (HPMC)
Tablets Avicel PH301, Eudragit E- 100, RLPO in
ethanol or acetone, or PVP and Tween
20 in deionized water.
Binder jet
printing
Orodispersible
tablets
Microcrystalline cellulose (MCC),
glycerine, Tween 80, povidone,
sucralose
SSE Bi- layered
tablets
Polyacrylic acid (PAA), MCC and
sodium starch glycolate
(polypill)
SSE Multiactive
HPMC K15M (Methocel K15M) Drug content uniformity, drug release
tablets
(polypill)
SSE Multiactive
PEG 600, D- mannitol, cellulose acetate Hardness, friability, in- process
tablets
(polypill)
SLS Tablets Kollicoat® IR or Eudragit® L100– 55.
Additionally, Candurin® gold sheen
was added to aid the sintering process
print accuracy and precision,
dissolution testing
uniformity, layer adhesion,
dissolution rate
Print accuracy and precision, print
resolution,
powder bed uniformity, dissolution
rate
Binder compatibility, drug content
uniformity,
dissolution rate
Disintegration time, disintegration
and erosion prole, drug content
uniformity, dissolution rate
Mechanical properties, drug- release
prole
proles
print accuracy and precision, physical
integrity and mechanical strength
monitoring
dissolution
Dissolution rates (geometry matters)
(continued)
newgenrtpdf
Advancements in Tailoring Medication
13
Соседние файлы в папке Библиотека им академика М.И. Перельмана