Volume 7, Issue 5, May – 2022 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165

Review: Novel Drug Delivery for the Treatment of

Osteoarthritis (OA)
Kajal Dev Raj Sharma, Vinay Pandit, M.S. Ashawat
Research scholar, Assistant Professor, Department of Pharmaceutics,
Laureate Institute of Pharmacy, Laureate Institute of Pharmacy,
Kathog, Jawalamukhi, Kathog, Jawalamukhi,
Himachal Pradesh 176031, India Himachal Pradesh 176031, India.

Abstract:- As people live longer, the prevalence of

osteoarthritis has increased, making it the most frequent
kind of arthritis. During osteoarthritis, tissue of cartilage
on articular joints corrodes, causing pain and sometimes
debilitating loss of function in patients. The most
significant risk factor for osteoarthritis is getting older.
Osteoarthritis, is the most common chronic joint illness,
and becomes common nowadays as people become older.
It disturbs the majority of people over 65 and is a main
musculoskeletal reason of reduced mobility in the
elderly. Because the particular molecular mechanisms
behind the degradation of cartilage matrix and the
development of OA are unknown, there are presently no
viable therapies to slow the advancement of OA or
prevent irreversible cartilage degradation other than
total joint replacement surgery. The major molecular
pathways involved in OA pathogenesis will be discussed
in this study, as well as new insights into prospective
molecular targets. Various Novel carrier are used to
enhancement of drug delivery to the site of action.

Keywords:- Osteoarthritis(OA),Aging,
Cartilage,Distruction,Nanocarrier.

I. INTRODUCTION Fig. 1: Shows a normal/healthy joint and a joint affected

with Osteoarthritis
The most common category of disease arthritis is (OA)
osteoarthritis(1). OA mainly disturbs the joints of the hip, According to the 3rd Nutrition Examination and
knee and hand and is induced by articular cartilage National Health Survey, approximately 37.4 percent of
deterioration and subsequent synovitis.(2). Obesity, genetic persons aged 60 and up in the United States had
susceptibility, and joint injury are all responsible for the radiographic evidence of OA(7).OA is a primary
development of osteoarthritis(3).Osteoarthritis is most musculoskeletal reason of reduced mobility in the old aged
common causes of chronic impairment in older people(4). In people, affecting joints such as knees, wrists, hips, and
many patients, functional impairment and discomfort can spine(8). While various risk factors for osteoarthritis have
lead to depression and significant sadness (3). The disease's been proposed, such as genetic susceptibility, ageing, joint
prevalence is expected to rise as the world population's misalignment and obesity, the pathophysiology of
lifespan lengthens.(5). It's a cartilage condition, which osteoarthritis is still not clear(9). Stiffness, joint deformities,
affects the smooth rubbery cushion that surrounds the joint's stiffness, chronic pain, radiographic joint space constriction
bones. (6).Osteoarthritis causes cartilage breakdown, which and joint instability are the most common clinical
is linked to damage to the menisci and other joint complaints(10).
components, as well as bone remodeling.
The risk factors of osteoarthritis have been identified
as: Genetic, Susceptibility, Age, Obesity, Joint
misalignment, and among others(11).

Clinical symptoms: Stiffness, joint deformities,

stiffness, chronic pain, radiographic joint space narrowing,
Redness(12).

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II. RISK FACTORS

Fig. 2: Various risk factors of osteoarthritis

III. TYPES OF OSTEOARTHRITIS clinical indications of osteoarthritis early with more

intensity(17).
 Primary Osteoarthritis: Its pathogenesis is unidentified;  PATHOPHYSIOLOGY: Members of the
though, a complex etiology involving the contact of local metalloproteinase and disinterring with MMPs and
and systemic components is most likely(13). thrombospondin motif' (ADAMTS) family, which
 Secondary Osteoarthritis: It is caused by degenerative breakdown collagen (MMPs) and aggrecan (ADAMTS),
variations in the joints as a consequence of identifiable respectively, are responsible for the degradation of
factors such as chronic or acute joint trauma, inflammatory articular cartilage(18). OA chondrocytes secrete greater
arthropathies (rheumatoid arthritis), muscle dysfunction, quantities of Tumor Necrosis Factor alpha (TNF)and
repetitive use and obesity(14). Gout and calcium deposits cytokines such IL-1, which can activate and induce these
in the joints .Many chronic comorbidities, like metabolic catabolic enzymes(19).It's not clear how important joint
syndrome, diabetes, and cardiovascular disease are now inflammation is in tissue degradation. Human OA is
being linked to OA(15). Factors linked to these related with mononuclear cell infiltration into the synovial
comorbidities, such as abdominal insulin resistance, membrane OA(20).There is a lot of evidence that the
dyslipidemias, increased blood pressure, obesity and are innate immune system is activated in illness(21). When
thought to play a main role in the onset and development inflammation is present, it accelerates tissue disintegration
of osteoarthritis (16).Furthermore, there is mounting and contributes to unpleasant illness episodes(22).
evidence that patients with comorbidities experience

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Cartilage

Fig. 3: Mechanisms underpinning the pathophysiology of OA. Multiple components are involved in the cellular and molecular
pathways that cause OA to die. Generally, cells in osteoarthritis joints emits higher levels of pro-inflammatory cytokines, causing
chondrocytes to secrete proteases that breakdown cartilage(23).

Fig. 4: Cartilage breakdown process in Osteoarthritis

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IV. DIAGNOSIS CRITERIA Other related indications include point tenderness,
stiffness of the affected joint lasting more than 30 minutes,
OA is diagnosed using a holistic assessment method deformity or enlargement of the joint, crepitus on physical
that includes a physical exam, radiographic scans, and/or exam, and a narrowing joint space and on radiography, this
detailed history(24). The quality of life, degree of function, was detected(29). It's crucial to remember that clinical
leisure activities, occupation, social networks, relationships symptoms and radiographic evidence are frequently at odds,
and mood of an individual should all be evaluated(25). QOL as not every person with radiographic signal of osteoarthritis
is frequently harmed in people with osteoarthritis, especially has significant clinical indications, and vice-versa(30)(31).
when the disease is advanced(26). The occurrence of bone
spurs or osteophytes on X-ray, joint pain and one or more Pain, edema, crepitus and stiffness in the afflicted
than one related indications, depending upon the affected joints are common presenting signs and symptoms of OA,
joint, are among the diagnostic criteria mirrored by the which are often convoyed by a loss in joint function or
OARSI(Osteoarthritis Research Society International)and movement limitation(32). Patients with OA of the knees
published by the ACR(American College of frequently describe knee instability, such as buckling or
Rheumatology)(27)(28). locking, especially when descending steps(33). The thumb is
typically affected by OA of the hand, making it difficult to
remove lids, turn keys, or grip an item with any vigor(34).

V. SELECTED RISK FACTORS OF OSTEOARTHRITIS IN KNEE HIP AND HAND

Knee Hip Hand References

Occurrence Age, sex, physical activity, BMI Physical Occupation, (35)(36)
(including obesity), strenuous sports activity,age,BMI grip, strength,
activities, quadriceps strength, bone (together with obesity), age, and
density, past injury, and hormone past injuries, strenuous heredity are all
replacement therapy are all factors to sports activities, and factors to
consider. heredity are all factors to consider.
Vitamin D, smoking, and (protective) consider (together with
(protective or deleterious), congenital deformities)
Genetics, misalignment (together with
valgus and varus), and malalignment
Progression Age, BMI (together with obesity), Age, symptomatic Unknown (37)(38)
hormone replacement therapy activity, sex, and high-
(protective), vitamin D, misalignment intensity sports activities
(together with valgus and varus), are all factors to
synovitis, chronic joint effusion, consider.
strenuous sports enterprises, and
subchondral bone oedema on MRI are all
factors to consider.
Table 1

VI. SYMPTOMS including diabetes, hypothyroidism and

hyperparathyroidism (44).When the symptoms of fever or
 Pain: When discomfort is present, it might be unilateral or infection (redness, warmth and soreness) are present, a
symmetrical, and it can worsen with exercise, especially systemic disease or an infection should be considered, and
weight-bearing activity. It is frequently relieved by a referral for joint aspiration to eliminate infection or
relaxation. Insidious pain with varied degrees of intensity crystalline arthritis should be made right away(45).
may develop around the afflicted joint(39). Constant pain, Calcium pyrophosphate deposition, rheumatoid arthritis,
which is linked to more severe disease, makes regular inflammatory arthropathies(also called as pseudo gout),
function and nighttime sleep difficult. Mention torture in arthritis and Reiter's syndrome linked with inflammatory
the buttocks, groyne, knee or thigh is a common symptom bowel illness should all be considered when swelling is
of hip OA(40). evident(46).
 Stiffness: Stiffness is a common complaint among  Crepitus: Finally, the crepitus is a crunching, grating
patients, especially when they first wake up after a period sound or crackling felt on palpation and heard with passive
of inactivity (gelling phenomena) or in the morning(41). scale of motion(47). The presence of crepitus may or may
This indication usually goes away after 20 to 30 minutes. not be related with pain. It develops as the joint cartilage
The stiffness is frequently relieved by moving the affected degenerates, causing opposing the surface of bones to
joint(42). grind against one another(48).
 Swelling: At first, joint swelling, or effusion, is common,
but it's vital to eliminate any recent trauma or distant as a
source of joint pain or swelling(43). Swelling in the joints
has been linked to a number of systemic diseases,

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VII. TREATMENT be useful in avoiding ulcer formation in the gastric
system(60).
 Topical agents: Capsaicin cream applied topically may
give relief from local pain for patients with osteoarthritis NSAID’s would be avoided during pregnancy,
of the hand that systemic pain relievers cannot, especially especially in the 1st and 3rd trimesters. (61). NSAID’s
during the flare-ups(49). It’s not, however, advised for hip usage in the 1sttrimester has been related to an increased
or knee OA. Capsaicin cream is accessible in the risk of miscarriage, whereas NSAID’s use in the 3rd
concentrations of 0.25 percent, 0.075 percent, and 0.025 trimester has been related to premature fetal renal
percent over-the-counter(50).To avoid the spreading of impairment, ducts arteriosus closure, platelet aggregation
cream to the mucous membranes or eyes, the patient must inhibition, and labour and delivery delays(62). If the
be advised to apply it with the help of gloves to the potential benefits outweigh the hazards, highly protein-
affected joint(51). Local burning and skin irritation are the bound formulations such as naproxen or ibuprofen are
most common side effects of capsaicin cream(52). favored if administered during lactation(63).
 Analgesics: For mild to moderate pain of osteoarthritis,  Opioids: It containing analgesics like oxycodone or
(Tylenol) acetaminophen is indicated as the first-line codeine (Roxicodone, Oxecta,Oxycontin)are used to
treatment, with a daily dose of 4,000 mg (maximum) relieve moderate to severe pain for brief periods of time to
divided into two doses for adults(53). Acetaminophen is cure acute exacerbations of pain and/or moderate to severe
tolerated in most people at the suggested doses because of pain(64).Due to an elevated hazard of possibly
its low risk of gastrointestinal damage. When used catastrophic or even fatal cardiac rhythm problems, the
excessively, however, hepatotoxicity can opioid propoxyphene (Darvon), which was previously
occur(54).Excessive acetaminophen use is linked to taking used to treat moderate to severe osteoarthritis pain, is no
higher-than-recommended doses, using it for an extended longer accessible in the US(65). To minimize the
period of time, or using it in conjunction with other development of drug tolerance and drug dependency, it is
acetaminophen-containing medicines(55). As a result, advisable to take these medicines for the short duration
liver enzymes should be constantly watched, and patients possible at the minimum effective dose for relief from
must be educated on how to take acetaminophen correctly pain(66). Because of the danger of dizziness, drug-to-drug
and avoid using other acetaminophen-containing interactions, falls in older persons and constipation caution
medicines at the same time. In addition, people with should be exercised when giving these medications(67).
kidney illness should use acetaminophen with caution.(56) Tramadol (Conzip, Ultram) is a synthetic opioid agonist
 Anti-inflammatory agents with analgesic properties: that works centrally to change a patient's observation and
NSAID’s (oral) are indicated for managing the pain response to the pain(68).
related with OA when acetaminophen does not provide  Intraarticular shots: Intraarticular shots of corticoids
adequate relief(57). The minimum active dose for the short like as triamcinolone or methyl prednisolone have been
time must be utilized to limit the hazard related to demonstrated to be beneficial for painful flare-ups of
comorbidities like GI, cardiovascular, liver issues or renal, osteoarthritis of the knee(69). Due to the uncommon
and the benefits must outweigh the dangers(58). In grown- chance of cartilage injury, an affected joint should not be
up adults, people with major comorbidities and people inserted more than 3 times in a span of year(70). Patients
who are taking other drugs that cause GI difficulties, who need injections more frequently may benefit from
caution is advised. While on NSAID therapy, the surgical intervention(71).
American Academy of Orthopedic Surgeons
recommended that patient’s liver and renal function testing Because they enhance the thickness of the synovial
be monitored each 6 months(59). fluid in between the joint area, intraarticular shots of
hyaluronic acid derivatives (Synvisc, Hyalgan), which
For individuals with a history of upper- may be effective in the treatment of pain in joints affected
gastrointestinal indications, a Histamine–H2 receptor by osteoarthritis(72)(73)(74). Inflammation and Joint pain
blocker or a proton pump inhibitor is indicated to lower can be reduced within 3-5 weeks of starting weekly doses,
the risk of duodenal ulcers, but this has not been proved to and the effects can last up to a year(75)(76).

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VIII. TREATMENT OPTIONS FOR OSTEOARTHRITIS BASED ON THE INTERNATIONAL
GUIDELINES OF THE OSTEOARTHRITIS (OA) RESEARCH SOCIETY (IF AVAILABLE)

Characteristics Treatment Osteoarthritis Research References

Society International
Guidelines Recommendation
Modifiable risk Factor Loss of weight Appropriate (77)(78)
reduction Exercise Appropriate: both in the water
and on land, with a focus on
strengthening
Bracing and physical Crutches Appropriate for knee-only (79)
modalities Cane osteoarthritis Undefined
Biomechanical interventions Appropriate
Alternative therapies Tai Chi No reference (80)(81)
Balneo therapy/spa Appropriate with individuals
with multiple joint
osteoarthritis
Acupuncture Undefined

NMES Undefined with knee-only

osteoarthritis

Cognitive behavioral therapy Suitable

Self-management and Not suitable

education
Ultrasound Uncertain in knee-only
osteoarthritis, otherwise
unsuitable
TENS No recommendation
Electromagnetic field therapy Uncertain in knee-only
osteoarthritis, otherwise
inappropriate
Laser therapy No reference

Pharmacologic (oral) Avocado Undefined (82)(83)

Acetaminophen Appropriate depending on
comorbidities
Glucosamine/Chondroitin Undefined
Soybean unsaponifiable Undefined for symptom relief, not
suitable for disease modification
Undefined in knee-only osteoarthritis
Duloxetine Suitable with multi joint
osteoarthritis.
Diacerein Undefined
Suitable in those without important
Opioids comorbidities
NSAIDs Undefined
Not suitable
Rosehip
Risedronate

Pharmacologic (topical) NSAIDs Suitable in knee-only osteoarthritis (84)

uncertain in multi joint osteoarthritis
Suitable in knee-only osteoarthritis

Capsaicin No reference
Uncertain
No reference
Topical NSAID’s
Opioids

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Tramadol
Pharmacologic (intra Hyaluronic acid Undefined in knee-only osteoarthritis, (85)
articular) not appropriate in multipoint
osteoarthritis
Corticosteroids Suitable

Table 2

IX. NOVEL DRUG DELIVERY FOR THE Liposome are closed vesicles structures composed of
TREATMENT OF OSTEOARTHRITIS bilayer of phospholipids and cholesterol intended for the
effective delivery of drugs and antigen having ability to
In current years, medication delivery with a regulated encapsulate both hydrophilic as well as lipophilic
rate and focused distribution has gotten a lot of molecules, allowing them to entrap wide spectrum of
attention(86). The use of nanotechnology to medicament has pharmaceuticals(98).Water loving molecules can be
resulted in the expansion of multifunctional nanoparticles entrapped in the aqueous (water) core, whereas
that can be loaded with various medications and act as drug hydrophobic molecules are introduced into the double
carriers(87).Nanocarriers provide a potential method to drug layer membrane(99).
delivery, with qualities such as drug protection against
cleavage and degradation, controlled release in the case of
targeted delivery systems, drug molecule distribution to the
target areas(88)(89).
 Niosomes:Niosomes, having double layer structure which
are generated by the self-assessment of cholesterol and
nonionic surface acting agents (surfactants) in an water
phase, which are one of the most capable drug
carriers(90). Niosomes are non-immunogenic,
biocompatible and biodegradable. They have an extended
shelf-life, are very stable and allow for regulated and/or
continuous drug administration at the target
location(91).The capability of niosomes as a medication
Fig. 6: Structure of Liposome
carrier has been actively researched in current years.
Various nonionic surface acting agents (surfactants) have  Transferosomes: Transferosomes have a structure that
been found to create niosomes, which allow for the combines hydrophobic and hydrophilic moieties; they may
trapping of a wide spectrum of medicines with varying accept medicinal molecules with a wide series of
solubility’s (92).To enhance the effectiveness of niosomes solubility(100). Transferosomes may bend and pass
for drug delivery, surface charge, number of lamellae, size through constriction up to ten times smaller than their own
and the composition of niosomes can be altered and area without noticeable loss. This high deformability gives
improved(93). improved diffusion of intact vesicles(101).Transferosomes
are self-assemblies with an ultra-flexible membrane that
distributes the medication into or through the skin in a
consistent manner(102).

Fig. 5: Structure of Niosome

 Liposomes:The well-studied and most prevalent Fig. 7: Structure of Transferosomes

nanocarriers for the targeted medication delivery are
liposomes. By stabilizing the therapeutic chemicals,  Ethosomes:"Ethosomes are ethanol liposomes, and these
overwhelming barriers to the tissue and the cellular are noninvasive drug delivery vehicles that allow
absorption, and enhancing bio-distribution of drugs to medications to penetrate deeper into the systemic
target areas in vivo, they have enhanced therapeutics for a circulation and/or epidermal layers(103).Ethosomes are
variety of biomedical applications(94)(95)(96)(97). vesicles of lipids that contain high concentration of

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alcohol (isopropyl alcohol and ethanol), phospholipids and  Transethosome: The term "Transethosome" refers to a
water. Ethosomes are soft kind of vesicles composed of hybrid of the terms "transferosomes" and "ethosomes."
ethanol (in greater amounts), phospholipids and water. Transferosomes demonstrate skin penetration as well as
Ethosomes range in size from tens of nm (nanometers) to the ability to deform(106). Transethosome can be taken
microns, and they penetrate the layers of skin quickly and by systemic as well as topical route. This device is capable
have much higher Transdermal flux(104)(105). of trapping drugs with molecular weights ranging from
low to high(107).Because the bioactive substance is
encapsulated, its content is released in a slow and
progressive way. It has a very effective trapping capability
due to its biocompatible and biodegradable nature. Its
development does not involve the use of any superfluous
medicinal components, nor does it necessitate a lengthy
process(108).

Fig. 8: Structure of Ethosomes

X. COMPARISON OF VARIOUS NANOCARRIERS IS SHOWN IN TABLE

S.no Carrier Advantages Disadvantages References

1. Niosomes Non-ionic surface acting agents Less skin penetration easy (110)
(surfactants) vesicles handling but will not able to
reach up to deeper skin layer
stable
2. Liposome’s Biocompatible, Phospholipid vesicle Less skin penetration (109)
3. More stable, higher permeation owing to None, but for some limitations (111)
Transferosomes biodegradable and biocompatible,
deformability, suited for both high and
low molecular weight medications, as
well as lipophilic and hydrophilic
pharmaceuticals, and able to penetrate
deeper into the layers of skin.
Transdermal medication delivery with Product loss occurs with the (112)(113)
improved drug permeability via the skin. transition of products from
The formulation's raw materials are non- alcoholic to non-alcoholic
toxic by nature. media.
4. Transethosome More stable Contact dermatitis can cause
skin irritation or an allergic
The semisolid version of the response.
transethosomal medication is used for Transethosomesmay Coalesce
administration. if vesicle production fails.
First-pass metabolism is avoided.
First-pass metabolism is avoided.
Table 3

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Fig. 9: Shows how the nanocarriers act on the infected joint in osteoarthritis

XI. SUMMARY AND CONCLUSION risk factors and microstructural changes. Arthritis
Res Ther. 2013;15(6):1–12.
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