**3.2 The superiorities and limitations of dermal and transdermal delivery**

There are two pharmacological approaches in dermal administration of drugs, which are dermal and transdermal. In dermal administration, the applied formulation ensures localization of drugs in dermal layers. In transdermal administration, the drugs reach the dermis of skin via carrier systems and then go into systemic circulation (Williams, 2003).

In dermal administration, the access of drugs to systemic circulation is prevented or minimized. Therefore, the systemic adverse effects of drugs are avoided. The advantages of transdermal administration include high patient compatibility with treatment, ability to discontinue treatment any time necessary, delivery of drug to organism at a controlled rate, ensuring fixed plasma drug level and eliminating the hepatic first-pass effect (Guy, 1996).

NSAIDs administered dermally and transdermally penetrate slowly and in small quantities into the systemic circulation. These approaches also prevent high local drug levels in the alimentary tract and direct toxicity of NSAIDs e.g. vomiting, dyspepsia. Systemic administration of NSAIDs may cause drug-drug interactions. NSAIDs cause fluid retention in the body and may decrease efficacy of antihypertensive agents. Furthermore, dermal and transdermal formulations have better patient compliance (noninvasiveness) and they can be self-administered (Guy, 1996; Taner & Marks, 2008; Heynemann et al., 2000). It was reported that the use of dermal NSAIDs may have led to a reduction in the total daily dosage of systemic NSAIDs. This would cause an increment in side effects of NSAIDs in long term treatment (Sift Carter et al., 1997). Finally, dermally applied NSAIDs have a superior safety profile to oral formulations. Adverse effects secondary to dermal NSAID application occur in approximately 10 to 15% of patients and are primarily cutaneous in nature (rash and pruritus at the site of application (Heynemann et al., 2000)). NSAI drug concentration should reach therapeutic level in the synovial tissue, synovial fluid and intra-articular tissues during dermal application of NSAIDs. There are a number of factors that influence skin absorption of drugs. The greatest challenge for dermal penetration is SC, the uppermost layer of the skin, which as mentioned previously is the rate limiting step for epidermal drug transport. Therefore several formulation approaches are developed to improve its impermeability characteristics.

#### **3.3 Overcoming the barrier properties of the skin**

Several chemical and physical approaches are used to overcome the barrier property of the skin in dermal and transdermal administration of drugs. The most frequently used approach is to include chemical penetration enhancers in formulations. Recently, physical

Novel Formulation Approaches for Dermal and

**Etofenamate** 369,3 4.99

**Ketorolac** 255,3 2,1

Table 2. Continued.

**Lumiracoxib** 293,7 4,56 139-

**Substance Chemical Formula**

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 31

**Felbinac** 212,2 3,26 164°C 8 µg/ml 4.3 Pygall et

**Ibuprofen** 206,3 3,72 76°C 14 µg/ml 4,41 Hadgraft et

**Indomethacin** 357,8 3,10 155°C 25 µg/ml 4,18 Hadgraft et

**Ketoprofen** 254,3 2,81 94°C 150 µg/ml 4,23 Hadgraft et

**Predicted Log P**

**Melting Point**

> 130– 135°C (bp)

165- 167°C (trometh amine salt)

25 mg/mL (trometha mine salt)

141°C 5,49 µg/ml 15,87

3,5

**Predicted aqueous solubility (µg/ml)**

Practically insoluble in water

**pKa References**

http:// www.chem base.com

al., 2009

al., 2000

al., 2000

al., 2000

http:// www.drug bank.ca

http:// www.drug bank.ca

**Molecular Weight (g/mol)**

Table 2. Chemical formulas and physicochemical properties of NSAIDs.

**Bufexamac** 223,3 2,43 154°C 110 µg/ml 9,24 Hadgraft et

**Diclofenac** 296,1 3,28 157°C 12 µg/ml 4,18 Hadgraft et

**Flurbiprofen** 224,3 4,12 110,5°C 2,7 µg/ml 4,14 Hadgraft et

**Etodolac** 287,4 2,5 145°C 16 µg/ml 4,65

Table 2. Chemical formulas and physicochemical properties of NSAIDs.

**Predicted Log P**

**Melting Point**

**Predicted aqueous solubility (µg/ml)**

158°C 3,3 µg/ml 11.1

**pKa References**

Avdeef et al., 1998. Quane et al.,1998

al., 2000

http:// www.drug bank.ca

al., 2000

http:// www.drug bank.ca

al., 2000

**Molecular Weight (g/mol)**

**Benzydamine** 309,4 3.71 160° (bp) - 9,27

**Celecoxib** 381,4 3,5 157-

**Substance Chemical Formula**

Table 2. Continued.

Novel Formulation Approaches for Dermal and

**Tenoxicam** 337,4 1,82

**Valdecoxib** 314,4 3,32

circulation (Neubert, 2011; Benson, 2005).

**3.3.1 Chemical enhancers**

**Substance Chemical Formula**

**Tiaprofenic**

Table 2. Continued.

Transdermal Delivery of Non-Steroidal Anti-Inflammatory Drugs 33

**acid** 260,3 2,42 96°C 450 µg/ml 4,05 Hadgraft et

methods such as iontophoresis that enhance penetration of drug molecules through the skin are applied (Mitragotri et al., 2000; Tao & Desai, 2003). Furthermore, vesicular carriers, microemulsions, lipidic and polymeric particulate carrier systems ensure dermal administration of drugs by dermal targeting and enterance of drugs into systemic

Chemical penetration enhancers reversibly change the structure of the skin to improve the flux of drugs through the skin. The mechanism of action of penetration enhancers is explained by Lipid-Protein-Partition (LPP) Theory (Williams & Barry, 1991). According to this theory, penetration enhancers i) disrupt the lipid structure in intercellular domain of SC, or ii) denature or change the conformation of keratin in the intracellular domain and/or iii) improve drug partition to SC and thus establish a drug reservoir in SC to act (Williams&

2,82

162-

164°C 34,8 µg/ml 9,4

**Predicted Log P**

**Melting Point**

**Predicted aqueous solubility (µg/ml)**

1,22 211°C 277 µg/ml 13,63

**pKa References**

http:// www.drug bank.ca

http:// www.drug bank.ca

al., 2000

http:// www.drug bank.ca

**Molecular Weight (g/mol)**

**Salicylic acid** 138,1 2,4 158°C 2,24 g/mL 2,97

Table 2. Continued.

**Naproxen** 230,3 3,00 155,3°C 23 µg/ml 4,4 Hadgraft et

2,56

143-

1,79

2,79

3,83

**Piroxicam** 331,4 1,46 199°C 870 µg/ml 13,92 Hadgraft et

**Predicted Log P**

**Melting Point**

**Predicted aqueous solubility (µg/ml)**

250°C 7,15 µg/ml 4,08

144°C 18,2 µg/ml 6,46

96°C 256 µg/ml 9,29

3,53 124,3°C 42,2 µg/ml 3,91

**pKa References**

http:// www.drug bank.ca

al., 2000

http:// www.drug bank.ca

http:// www.drug bank.ca

al., 2000

http:// www.drug bank.ca

**Molecular Weight (g/mol)**

**Meloxicam** 351,4 1,9 242 -

**Nimesulide** 308,3

**butazone** 324,4

**Suprofen** 260,3 3,16

**Oxyphen-**

Table 2. Continued.

**Substance Chemical Formula**

Table 2. Continued.

methods such as iontophoresis that enhance penetration of drug molecules through the skin are applied (Mitragotri et al., 2000; Tao & Desai, 2003). Furthermore, vesicular carriers, microemulsions, lipidic and polymeric particulate carrier systems ensure dermal administration of drugs by dermal targeting and enterance of drugs into systemic circulation (Neubert, 2011; Benson, 2005).


**1. Introduction**

Appendicitis is an inflammation of the vermiform appendix, which presents as one of the causes of acute abdomen leading to emergency surgical indication. The acute appendicitis presented as the most common indication of nontraumatic emergency surgeries around the world. Annually, more than 100 cases of appendicitis per 100,000 persons are recorded around the world. About 16.33% of men and 16.34% of women mostly in the second and third decades of life were at risk of experiencing acute appendicitis [1, 2].

More than 108,000 surgical procedures were conducted to treat appendicitis in a year. Acute appendicitis may be treated with surgical treatment and conservative treatment. Treatment choices were considered in acute appendicitis by classification of clinical uncomplicated or complicated appendicitis occurred [3].

Distinguishing indications of surgery or appendectomy as treatment of appendicitis might be challenging. It was more subtle in pediatric patients, as more consideration and careful examination needed to be conducted prior to the surgical procedure. Statistics had recorded more events of negative appendectomy, the fact that vermiform appendix presented to be normal or not inflamed after the process of appendectomy. The incidence was commonly only about 15% in adults but raised up to 56.7% or even more in pediatric patients presenting with related symptoms to appendicitis. These procedures were stated as a burden in medical decision-making as non-indicative surgeries may harm patients or even cause expenditures for non-beneficial procedures [4].

The main aim of diagnostic and decision-making in appendicitis was to accurately distinguish any chance of currently symptomatic appendicitis appearing normal as presented during operation. This means that appendicitis may be reversible and basic inflammation of the appendicitis was not causing permanent damage to the appendix vermiform itself. Currently, there was still no such strong evidence to prove whether an appendicitis process that occurred would end as permanent tissue damage and causes complications that are mandatory for surgical treatment of the appendix vermiform or would heal without risk of complications [5].

We analyzed the possibilities of differentiation of the two conditions in appendicitis. The main key to understand and accurately differentiate risk in appendicitis would be clearly explained in a basic inflammatory mechanism on how appendicitis would occur. The promising approach was glancing at the pathways and mechanism of inflammation would occur specifically, as related with factors lying alongside the pathophysiological process of inflammation and cure of the inflammation itself, by sufficient oxygenation and adequate metabolism of remodeling or tissue repair.


**4. Sustainable development**

### **4.1 Manure handling and management**

Some researchers [1] reported that industrialized beef and dairy cattle production concentrated manure on limited land areas. A small proportion of the cost of production (about 3 %) was usually spent as cost of manure removal in large farms. Manure was usually applied as fertilizer on crop land and most of the manure needed to be well managed so as not to pollute the land surface water and the atmosphere through the volatilization of gases (GHG) and odours.